目 录

一、导语 .......................................................................................................................................... 1

二、4 月份中国机构 CNS 发文与学术领域热度 .......................................................................... 1

三、4 月份城市&地区在 CNS 的论文和影响因子 ....................................................................... 3

四、4 月份中国机构发文 CNS 的走势 .......................................................................................... 4

五、4 月份 CNS 发文机构论文量统计 .......................................................................................... 4

六、4 月份 CNS 论文通讯作者的项目数和经费 .......................................................................... 6

七、受关注的权威看法 ................................................................................................................... 8

八、专家精选 ................................................................................................................................ 11

九、4 月份论文列表...................................................................................................................... 16

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一、导语

自然系列期刊在 2013 年的论文统计显示，中国科学院超过日本东京大学排名亚洲机构第一

位，这也是 Nature Index 统计以来中国科研机构多次排名第一，反映出中国顶尖科研机构在

数量上领跑亚洲。

在生物学领域，三大期刊（Cell、Nature 和 Science）及其子刊，简称 CNS，倍受中国研究

人员推崇，他们希望凭借 CNS 在学术界的威望将中国尖端、前沿的研究成果向全世界传达。

这些研究动态代表了中国科研机构的最高水平。生物探索希望对此进行统计，从发文成果追

踪国内科研经费动向，便于生物医药圈内的研究人员和学生能够实时了解中国顶尖研究人员

从事研究的领域和方向。

二、4 月份中国机构 CNS 发文与学术领域热度

（饼状图表示期刊论文百分数）

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2014年 4月份中国研究机构在三大系列期刊共发表 59篇论文，包括 Cell系列 24篇、Nature

系列 32 篇和 Science 系列 3 篇，其中 Nature 主刊，Science 主刊及 Cell 主刊的发文量分

别为 4 篇、3 篇和 0 篇。从发文比例上看，发表中国机构论文一直处于上位的 Nature 系列

期刊略低于 3月，Cell系类期刊发文数量较上月大幅增长，Science发文数量则突破了上月

0的记录，且在主刊上有 3篇文章发表。从地区上看，大陆地区仍然是中国机构发表 CNS论

文的主体，台湾地区本月发文量大幅上涨为 7 篇，香港地区发表文章数量与上月持平为 1

篇，澳门地区则突破零的记录为 1篇。

4月份 CNS发表的中国机构研究论文中，分子生物学领域（23篇）排在第 1位，细胞生物学

排在第二位，有 13篇文章入列，基因组学有 9篇文章入列。从学术热度上看，2014 年 4 月

3 日，由上海瑞金医院、深圳华大基因研究院等单位组成的科研团队，通过对 57例 ACTH 非

依赖性库欣综合征（Adrenal Cushing's syndrome）患者的肾上腺皮质肿瘤样本进行全外显

子和转录组测序，发现了 PRKACA 基因上 L205R 热点突变与肾上腺瘤发病密切相关，并且

发现了 DOT1L 和 CLASP2 与其他亚型的关联，为肾上腺皮质肿瘤及 ACTH 非依赖性库欣综

合征的诊断、治疗提供了新思路。该研究成果发表在《科学》（Science）杂志上。

另外，北京大学生命科学学院魏文胜等在细菌毒素侵染宿主机制方面获得重要进展。该课题

组开发了一种基于 CRISPR/Cas9系统的慢病毒聚焦型人源细胞文库、功能性基因筛选平台以

及基于高通量深度测序技术解析数据的完整技术路线。研究人员可利用这一高效的新型遗传

筛选技术，成功鉴定出对两种细菌毒素侵染宿主所必需的宿主受体以及多种新型蛋白位点，

从而不仅能够帮助人们研究与病菌侵染相关的宿主蛋白及通路，还可以惠及众多生物医学相

关领域的研究。这项具有里程碑意义的工作是在激烈的国际竞争中完成，与已经在《科学》

杂志发表的两篇主题相近的文章比较，该工作所报道的方法具有更为广泛的细胞系适应性，

对于功能性基因的筛选和鉴定具有十分重要的意义。相关研究成果 4月 9日在线发表于《自

然》杂志上。

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三、4 月份城市&地区在 CNS 的论文和影响因子

（影响因子源自 MedSci 查询系统，取小数点后一位）

从 CNS 论文影响因子看，4 月份北京以 266.405 分卫冕排行榜，从上图可以看出，上海以

134.928 分居第二，北京和上海的 CNS 论文影响因子领先其它城市&地区。

在 2014 年 4 月份，北京（15 篇）和上海（12 篇）是发表 CNS 论文较多的城市，而其它城

市&地区发表 CNS 论文数都不多。另外，本期 CNS 实际发文量 59 篇。

对城市&地区的 CNS 影响因子统计，生物探索网站希望向用户提供关于地区研究水平的一

项指数，让科研人员在从事各自研究领域的同时选择较高的研究平台和学术氛围。此外，由

于论文来自不同的经费项目，因此城市&地区的 CNS 影响因子能从一个方面反映国家经费

的分配比例。

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四、4 月份中国机构发文 CNS 的走势

（数据统计源自 NCBI 网站 Pubmed）

对 2013 年 11 月至 2014 年 4 月中国机构发文 CNS 进行统计，数据表明：Nature 及其子刊发

表的中国研究论文数量处于高位，总计 176 篇，月最高发文量达到 35 篇。相比较而言，Science

及其子刊发表一直处于中国研究论文数量的低位，总计 9 篇，其月最高发文量为 3 篇。Cell

及其子刊共发表的文章数量为 70 篇，本月较上月大幅增长。

五、4 月份 CNS 发文机构论文量统计

研究机构 CNS论文

4月份发文量 近 5年总数 总数

中国科学院上海生命科学研究院 5 189 357

北京大学 3 151 228

中国科学院生物物理研究所 1 87 199

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清华大学 3 139 196

复旦大学 1 105 152

中国科学院动物研究所 7 86 148

上海交通大学 5 100 130

台湾中央研究院 1 61 130

中国科学技术大学 1 63 99

南京大学 1 64 97

浙江大学 2 66 90

第二军医大学 3 54 90

中国医学科学院基础医学研究所 3 38 87

国立台湾大学 2 51 84

中山大学 1 56 75

香港大学 2 47 70

厦门大学 2 49 65

四川大学 1 42 61

武汉大学 1 39 58

中国科学院遗传与发育生物学研究所 1 33 57

香港科技大学 1 28 56

华中科技大学 1 29 51

国立阳明大学 1 28 46

北京生命科学研究所 1 29 44

第三军医大学 2 27 34

南京医科大学 1 22 34

中国科学院上海药物研究所 2 17 32

深圳华大基因 1 25 30

南开大学 2 23 28

中南大学 1 13 26

台湾长庚大学 1 14 22

第四军医大学 1 14 20

南方医科大学 1 11 15

天津医科大学 1 10 15

首都医科大学 1 11 14

暨南大学 1 3 13

台湾国家卫生研究院 1 9 12

大连医科大学 3 8 12

台北医学大学 1 7 10

云南大学 1 6 9

西北农林科技大学 1 5 5

华南师范大学 1 4 5

长荣大学 1 2 2

澳门大学 1 2 2

澳门科技大学 1 2 2

（数据源于NCBI网站Pubmed）

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从4月份中国机构CNS论文榜单上看，排名前三的分别是中国科学院上海生命科学研究院、

北京大学和中国科学院生物物理研究所。针对每个机构的发文量，超过 1 篇的研究机构是中

国科学院动物研究所（7 篇）、中国科学院上海生命科学研究院（5 篇）、上海交通大学（5

篇）、北京大学（3 篇）、清华大学（3 篇）、浙江大学（2 篇）、第二军医大学（3 篇）、中国

医学科学院基础医学研究所（3 篇）、大连医科大学（3 篇）、国立台湾大学（2 篇）、香港大

学（2 篇）、厦门大学（2 篇）、第三军医大学（2 篇）、中国科学院上海药物研究所（2 篇）、

南开大学（2 篇）。

在 4 月份 CNS 论文的统计数据中，发表 CNS 论文数量共 59 篇，这些机构均不是首次发文。

其中，西北农林科技大学、长荣大学、澳门大学、澳门科技大学的 CNS 论文全都在近 5 年

内。

六、4 月份 CNS 论文通讯作者的项目数和经费

研究机构 项目作者 研究经费（W） 项目数（个）

中国科学院生物物理研究所 朱平 3250 4

上海交通大学&中国科学院上海生命

科学研究院 宁光 2384.6 11

清华大学 中国科学院动物研究所 孟安明 2163.3 18

南京大学 王炜 1880.5 17

中国医学科学院基础医学研究所 第

二军医大学 浙江大学 曹雪涛 1860.4 20

中国科学院上海生命科学研究院 谢东 1607 9

中国科学院遗传与发育生物学研究所 傅向东 1539.8 8

军事医学科学院放射与辐射医学研究

所&大连医科大学 张令强 1160 10

中国科学技术大学 施蕴渝 1083.5 9

上海交通大学 王卫庆 956 5

北京大学 邓宏魁 930 9

中国科学技术大学 吴季辉 914.5 7

北京大学 尹玉新 784 3

华南师范大学 邢达 718.6 8

中山大学 大连医科大学 刘强 614 8

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中国科学院动物研究所 王昆 529 9

华大基因 澳门科技大学 香港大学 王俊 470 3

中国科学院动物研究所 李培峰 422 5

厦门大学 尹震宇 386 3

上海交通大学 李青峰 386 4

中国科学院上海生命科学研究院 韩敬东 386 3

南方医科大学 方唯意 383 8

四川大学 李沁桐 382 3

上海交通大学 童建华 365 12

中南大学 刘峰 345 3

第二军医大学 孙树汉 303 7

华中科技大学 陈晓钎 299 5

云南大学 侯先光 291 5

清华大学 杨茂君 270 2

第四军医大学 费舟 248.5 6

第三军医大学 张莉莉 228 8

清华大学 张林琦 200 1

上海交通大学 王艳 197 7

大连医科大学 姚继红 175 5

天津医科大学 张荣信 147 4

南开大学 刘林 145 2

南京大学 刘锋 141.5 7

北京大学 魏文胜 118 3

第三军医大学 甘立霞 102 7

中国科学院生物物理研究所 李国红 95 2

南京医科大学 王迎伟 95 4

复旦大学 何睿 93 2

北京生命科学研究所 王晓东 92 4

中国科学院动物研究所 李卫 90 2

大连医科大学 田晓峰 88 2

中国医学科学院基础医学研究所 王琳芳 70 1

清华大学 王新泉 67 2

厦门大学 王洪睿 64 2

厦门大学 张晓坤 61 2

8

中国科学院上海生命科学研究院 胡荣贵 56.5 3

暨南大学 陈填烽 48 2

武汉大学 孙宇辉 38 2

西北农林科技大学 曾文先 35 1

南方医科大学 吕晓智 34 1

第三军医大学 李敬诚 32 1

南开大学 朱玉山 26 2

（数据源于 NSFC）

对于 2014 年 4 月份中国机构发文 CNS 的 58 位通讯作者（统计量不完全），国家自然科学基

金项目提供了详细的项目金额和数量（从 1986 年至 2014 年）。中国科学院生物物理研究所

的朱平以 3250 万元高举榜首，项目数为 4 个；上海交通大学、中国科学院上海生命科学研

究院的宁光以 2384.6 万元位居第二，项目数为 11 个；清华大学、中国科学院动物研究所的

王明荣以 2163.3 万元位居第三，项目数为 18 个。

排名前 10 的通讯作者来自 4 个城市，分别是：北京（5 位）、上海（3 位）、南京（1 位）、

合肥（1 位）。其中，北京地区 5 位通讯作者位于项目金额榜前十位之内，这反映出北京位

列 4 月份 CNS 中国机构影响因子之首的经费基础。

七、受关注的权威看法

施一公：科研与创新并无捷径

施一公教授在瑞典斯德哥尔摩荣获了 2014 年的爱明诺夫奖。这个奖项在 1979 年由瑞典皇家

科学院所设，主要奖励给晶体学领域的科学家。施一公今年是唯一获得此奖的人。

9

早在 2008 年施一公放弃美国大学终身教授回国的时候，就曾引发过人们的关注。2010 年，

施一公和饶毅教授联合发文认为，中国政府投入的研究经费，以每年超过 20%的比例增加，

但是在现实中，研究经费分配中的严重问题，却减缓了中国潜在的创新步伐。近年来，科研

体制的改革一直在努力，科学家们取得了如此成就，也从侧面说明了科研体制改革在不断推

进，科研环境在不断优化。

相关媒体就施一公是谁做了一个小调查，受访公众被问道，“你知道施一公这个人和他的研

究领域吗？”不知道的人将近八成。接着，公众又被问道：“这个科学家的研究成果被应用

于一种抗癌新药，未来会造福很多的人，你愿意不愿意去了解他？”此时，可以去了解和非

常想了解的人超过了九成。

这充分显示了中国人的特性，注重实用性，甚至功利。在当下，还加上了物质主义这一重要

特性。坦率地说，这种对待科学和职业的态度，深深地根植于一些浮躁的物质主义氛围中。

尤其是在转型时期，旧的道德逐渐消逝，新的道德尚未形成，道德真空与监管漏洞导致了一

些暴富现象普遍发生，除了以往历史积淀下来的官本位思想，人们还欣赏于各种投机思想，

投机无处不在，股市、楼市，以及做企业。

当然，在一个多元化与多样性的时代，并不应该对人们的职业追求带着某种导向性评判，无

论是企业家、歌星明星，还是科学家，人们都可以视之为可奋斗的目标。关键是，社会应该

减少浮躁心态以及投机，一个良好的社会氛围应该是能够鼓励和奖励创新、奋斗，以及大部

分人都有通过自身努力能够获取成功的机会与可能。这或许也将是“中国梦”的组成部分，

人们靠的不是拼爹、暴富的机会、投机的想法，而是自己的努力、智慧以及拼搏获取成功。

兰迪·谢克曼：不恰当的激励会损害科学研究

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诺贝尔医学获奖者兰迪·谢克曼再次抨击 CNS，称 CNS 限制发文篇数和篇幅，给年轻学者带

来了很多不必要的压力，而且它逐渐成为衡量科研水平的唯一标准，正向"商品"转化，所以

他希望年轻学者不要成为这个制度的"受害者"和"牺牲品"，开放杂志是颠覆现有科研制度的

有力工具。以下为采访语录精选：

记者：您曾经说过，《自然》、《科学》和《细胞》用“不恰当的激励方式”来损害科学研

究进程，能否具体谈谈其不恰当主要体现在哪些方面？

谢克曼：首先，这些刊物对于文章发表的篇数、篇幅都有严格的限制，这些期刊把自己看作

是限量版的奢侈品，却忘了科学研究与论文发表的本义所在。很多年轻学者之所以急于将一

些不够成熟的论文提交出来，主要是受到这三大期刊的表面上那种“奢侈品”形象的诱惑，

而这些期刊限制发文的篇数和篇幅的种种形式上的门槛，又给了他们很大的压力。因为如果

不能迅速将这些文章发表出来，他们的科研生涯或许就此终结。

其次，眼下学界流行用影响因子来衡量期刊优劣。这将极大地误导年轻学者，让他们更倾向

于将论文投给那些所谓影响力大的刊物，而非那些最适合发表的地方。

记者：有观点质疑，您已获得了诺贝尔奖，因此可以公开“抵制”三大核心期刊。而对于大

多数青年科学家而言，他们仍需要借助这类期刊来增加其学术观点的传播力，您怎样看待上

述观点？

谢克曼：在我的学术生涯中，我也曾向这三大期刊投稿。所以，很多人骂我，我能理解他们

的批评。但是，现在的问题是不能纠缠于个人感情，而是必须对这种状况叫停！在功成名就

的科学家中，必须有人站出来，打破这个不合理的科研评价制度，让年轻学者不再像其长辈

那样沦为这种制度的“受害者”。我所做的，只不过是站在一个老科学家的角度，希望凭一

己之力，帮助那些科学界年轻学者，因为他们才是这个制度和体系的受害者。

记者：人们总是习惯用量化指标来衡量一件事情的优劣。如此以来，才有了考试分数、SCI

指数。在您看来，用什么样的标准才能完整地反映事物，我们应该建立一种怎样的科学成果

评价体系？

谢克曼：我对现在流行的衡量体系深表怀疑，影响因子存在先天的瑕疵。我认为，唯一衡量

论文质量的方法就是：人们应该完整地阅读全文，然后由自己来做出判断。值得一提的是，

对于很多严肃的科学期刊而言，除了极少数该领域的专业人士外，其他人或许很少有兴趣把

全文读完，我们的做法是，让一名该领域的科学家在仔细阅读后，对其进行概括，我们把这

段概括称作“eLife 消化”。每个阅读《eLife》的读者，都有机会能接触到这种概括性的

评价，并最终得出自己的评价。

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八、专家精选

Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon

phosphorylation by RIP3（北京生命科学研究所王晓东）

哺乳动物细胞的程序性死亡除通过凋亡通路以外还可借由程序

性坏死通路发生。细胞的程序性坏死由肿瘤坏死因子受体家族

以及 Toll-like 的受体家族启动，并通过和受体蛋白互作的两

个蛋白激酶 RIP1 和 RIP3 传递死亡信号。王晓东实验室在何苏

丹博士 2009 年发现了 RIP3 是在细胞程序性坏死通路必不可少

的信号传递蛋白后（He et al., Cell 137, 1100)，在过去的

几年中努力的去攻克蛋白激酶如何引起细胞坏死的难题。

他们实验室以孙丽明博士为主的团队和北生所陈涉与雷晓光实验室紧密合作，利用精密的蛋

白分析与化学生物学手段，在 2012 年发现了 RIP3的特异性底物蛋白 MLKL。MLKL 此前还从

未被报道过。他们发现 MLKL 是拥有激酶结构域但无激酶功能的假激酶，其激酶结构域的 375

位的苏氨酸和 358位的丝氨酸（人源）在细胞程序性坏死被启动后被 RIP3磷酸化。MLKL的

磷酸化是细胞程序性坏死通路中不可或缺步骤 (Sun et al., Cell 148, 213)。

在本期发表的 Molecular Cell 杂志封面文章中，王晓东实验室又详细描述了 MLKL 的磷酸化

是如何导致了细胞程序化坏死的分子机制。MLKL 的磷酸化使其从单体状态向多聚体状态的

转化。多聚化的 MLKL可以结合磷酸肌醇(phosphoinositides)和心肌磷脂(cardiolipn)，从

而由细胞质转移到细胞膜和细胞器膜上；并在这些膜结构中形成通透性孔道，从而破坏膜的

完整性，引起细胞坏死。

这篇文章同时介绍了王晓东实验室和 Epitomics 公司的科学家合作开发的能特异识别人源

MLKL 磷酸化的单克隆抗体；并证明这一磷酸化抗体可作为标识，用于检测在体外培养的人

源细胞和人体组织中细胞程序性坏死是否发生。王晓东实验室在和北京 302医院王福生教授

的合作中发现在药物引起的肝损伤病人活检组织中有明显升高的 MLKL 磷酸化信号，直接证

明了 RIP3/MLKL介导的细胞死亡程序在人类器官损伤性疾病中被启动了，具有重大意义。

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High-throughput screening of a CRISPR/Cas9 library for functional genomics in human

cells（北京大学魏文胜）

探索基因及其表达的蛋白在特定生理、病理、发育等过程中所

起的作用一直是生命科学领域研究的重要内容。尽管利用 RNA

干扰鉴定高等生物基因功能的技术已经普及，但是这种方法经

常伴随脱靶现象；而且由于只能部分抑制基因表达，往往不足

以造成表型变化从而影响对其基因型的判断。近几年基因编辑

技术的出现，使得对单一基因进行修饰的遗传手段得到迅速发

展，然而在哺乳细胞内基于基因完全敲除进行大规模功能性筛选的方法依然空缺。

北京大学生命科学学院魏文胜课题组为此开发了一种基于 CRISPR/Cas9 系统的慢病毒聚焦

型人源细胞文库、功能性基因筛选平台以及基于高通量深度测序技术解析数据的完整技术路

线。利用这一高效的新型遗传筛选技术，成功鉴定出对两种细菌毒素侵染宿主所必需的宿主

受体、以及多种新型蛋白位点。这一强大的高通量基因筛选技术的建立不仅能够帮助人们研

究与病菌侵染相关的宿主蛋白及通路，还可以惠及众多生物医学相关领域的研究。这项具有

里程碑意义的工作是在激烈的国际竞争中完成，与已经在《科学》杂志发表的两篇主题相近

的文章比较，该工作所报道的方法具有更为广泛的细胞系适应性，对于功能性基因的筛选和

鉴定具有十分重要的意义。

该项研究成果是与北京大学生物动态光学成像中心 (BIOPIC) 黄岩谊课题组合作完成的，4

月 9日在线发表于《自然》杂志 (High-throughput Screening of a CRISPR/Cas9 Library

for Functional Genomics in Human Cells)。其共同第一作者为北京大学生命科学学院魏

文胜课题组的博士研究生周悦欣、朱诗优和蔡昌祖。研究课题得到了国家重点基础研究发展

计划、国家自然科学基金和北大清华生命科学联合中心的支持。

IKKα restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation

（中山大学刘强）

鼻咽癌是一种发生于鼻咽粘膜的恶性肿瘤。占头颈部恶性肿瘤

的 78.08%。占上呼吸道癌肿的 92.99%。其具有原发部位隐蔽，

不易被早期发现，病理分化差，恶性程度高，易呈浸润性生长

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及早期转移的特点。我国是鼻咽癌发病率最高的国家，当前鼻咽癌的治疗以放疗为主，但疗

效上不理想，约 55%的鼻咽癌在放疗后 5年会出现复发转移。因此迫切需要寻找高效、无害

的新疗法。细胞低分化是鼻咽癌的一个重要特征，也为通过分化治疗干预疾病提供了一个独

特的机会。

来自中山大学、大连医科大学的刘强等研究人员在新研究中证实，通过抑制 EZH2 恢复 IKK

α 可诱导鼻咽癌分化。在这篇新研究中，研究人员采用 RNA 测序和功能分析方法证实，IKK

α 表达下降是导致鼻咽癌不分化表型的主要原因。他们证实过表达 IKKα 可在不激活 NF-κ B

信号通路的情况下诱导鼻咽癌细胞分化并减少癌细胞的致瘤性。

此外，研究人员还获得了一个重要的研究发现：EZH2通过控制 IKKα 启动子上的 H3K27 组蛋

白甲基化引导了 IKKα 转录抑制。分化诱导剂、维甲酸都可通过抑制 EZH2 介导的 H3K27 组

蛋白甲基化提高 IKKα 表达，从而促进鼻咽癌细胞分化。与之相一致，IKKα 低水平、EZH2

高水平表达与鼻咽癌患者样本不发生分化相关联。

这些研究结果证实了 IKKα 在鼻咽癌分化中起重要作用，并揭示了 IKKα 的一种表观遗传调

控机制，为鼻咽癌分化治疗指出了一条新途径。

The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell

differentiation（第二军医大学&中国医学科学院基础医学研究所&浙江大学曹雪涛）

长链非编码 RNA（lncRNA）是一类转录本长度超过 200nt 的

RNA 分子，起初研究人员发现它们并不编码蛋白，因此将它们

认作为是基因组转录的“噪音”，不具有生物学功能。然而，

近年来的研究发现， lncRNA 参与调控了机体的生长发育、细

胞凋亡、增殖、分化等，与多种疾病密切相关。但到目前为止

还只报道了少数调控免疫系统的 lncRNAs 。

树突状细胞（DCs）是哺乳动物免疫系统中最有力的抗原递呈细胞；它们的分化和功能对先

天免疫和适应性免疫应答具有重要的影响。尽管已经确定了一些转录因子和细胞因子在 DC

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细胞群的生成与稳态中发挥至关重要的作用，对于在 DC 分化和功能中起作用的非编码

RNA ，尤其是 lncRNAs 仍然知之甚少。

来自第二军医大学、中国医学科学院和浙江大学医学院的曹雪涛等研究人员，发现一种名为

lnc-DC 的长链非编码 RNA 控制了人类树突状细胞的分化。

在这篇新论文中，研究人员利用广泛接受的、诱导外周血单核细胞分化为人类树突状细胞的

模型，进行转录组微阵列分析和 RNA 测序，鉴别出了唯独表达于人类 DCs 中的一种长链非

编码 RNA: lnc-DC 。他们证实抑制 lnc-DC 可破坏体外人类外周血单核细胞以及体内的小

鼠骨髓细胞分化为 DC，并减小了 DCs 刺激 T细胞激活的能力。

进一步的机制研究证实， lnc-DC 是通过激活转录因子 STAT3 来介导这些效应的。 lnc-DC

直接结合到细胞质中的 STAT3 上，通过阻止 STAT3 结合 SHP1 及被去磷酸化，促进了

STAT3 tyrosine-705 位点磷酸化。新研究确定了一个调控 DC 分化的 lncRNA ，并扩宽了

已知的 lncRNA 作用机制。

Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal

units（中国科学院生物物理研究所李国红）

高等生物的遗传信息储存在染色体的 DNA中，每一个体具有 200

多种不同细胞，这些细胞都是从单个受精卵细胞发育分化而来

的，具有相同的遗传信息，但是他们的形态和生理功能却大相

径庭。研究表明，生命体通过调控细胞核内染色质结构（特别

是 30nm染色质高级结构）的动态变化来有选择性地进行基因的

激活和沉默，从而控制细胞自我维持或定向分化，决定细胞的

组织特异性和细胞命运，进而形成复杂的组织、器官和个体。

15

由于缺乏一个系统性的、合适的研究手段和体系，之前对于 30nm 染色质纤维这一超大分子

复合体的组装和调控机理的研究还十分有限，对于它的精细结构组成也具有很大争议。近

30多年来，30nm染色质纤维高级结构研究一直是现代分子生物学领域面临的最大挑战之一。

来自中科院生物物理研究所的李国红等研究人员利用低温电子显微镜（cryo-EM）技术，成

功建立了一套染色质体外重建和结构分析平台，利用一种冷冻电镜单颗粒三维重构技术在国

际上率先解析了 30nm染色质的高清晰三维结构，在破解“生命信息”的载体——30nm染色

质的高级结构研究中取得了重要突破。该结构揭示了 30nm染色质纤维以 4 个核小体为结构

单元；各单元之间通过相互扭曲折叠形成一个左手双螺旋高级结构（图 1）。同时，该研究

也首次明确了连接组蛋白 H1在 30nm染色质纤维形成过程中的重要作用，这项研究对于理解

细胞增殖、发育及分化过程中一些重要基因的表达差异及表观遗传学调控机理具有重大的意

义。

本研究论文的评审人评论说，“30nm 染色质结构是最基本的分子生物学问题之一，困扰了

研究人员 30 余年”，该结果是“目前为止解析的最有挑战性的结构之一”，“在理解染色

质如何装配这个问题上迈出了重要的一步”。

PTEN α , a PTEN Isoform Translated through Alternative Initiation, Regulates

Mitochondrial Function and Energy Metabolism（北京大学尹玉新）

PTEN 是重要的抑癌基因， PTEN 蛋白既可通过拮抗 PI3K/AKT

通路影响肿瘤细胞增殖和生长，也可直接进入细胞核内维持基

因组稳定性，在肿瘤抑制过程中发挥重要作用。越来越多的研

究提示 PTEN基因除抑制肿瘤外也参与神经、代谢等多种生物功

能的调控。

北京大学系统生物医学研究所尹玉新课题组最近研究取得突破，揭示了真核生物中新的蛋白

编码机制，并由此发现 PTEN 家族的新蛋白 PTENα ，进一步证实其定位于线粒体，参与调控

细胞能量代谢过程。这项发现首次阐明了真核生物可以通过不同密码子翻译起始合成不同蛋

16

白质亚型，从而大大增加了潜在蛋白质家族的数量和构成，有助于揭示蛋白质多功能的分子

机制，奠定生物多样性的物质基础。

研究人员发现，PTEN基因既可利用传统的 AUG编码启动子合成 PTEN蛋白，也可利用新型编

码启动子 CUG 合成新亚型 PTENα 蛋白。PTENα 与 PTEN 由相同 mRNA 上的不同翻译起始点翻

译而成。传统 PTEN蛋白由 PTEN mRNA上第 1032位的 AUG起始翻译，而 PTENα 则由位于 AUG

上游的 513位 CUG起始翻译产生，较 PTEN在 N-端延长 173个氨基酸。这一过程由真核翻译

起始因子 eIF2A启动，并依赖于 CUG周围形成发卡结构的回文序列，作为 CUG翻译起始的信

号，类似于 AUG的 Kozak序列。研究显示 PTENα 蛋白可定位于线粒体内，并与 PTEN 形成复

合物，直接调节细胞色素 C氧化酶 1（cytochrome c oxidase subunit 1, COX1），从而调

控线粒体活性和能量代谢过程。

研究人员还通过新型 TALEN 技术将 PTENα 特有编码区进行移码突变，从而实现 PTENα 的特

异性敲除。PTENα 的缺失导致细胞线粒体结构异常、氧化磷酸化复合物活性下降、ATP合成

减少。该研究成果揭示了 PTEN 基因的复杂性，对鉴定 PTEN 家族成员具有指导意义，并为

PTEN 基因直接调控线粒体代谢过程提供了重要依据 ，明确 PTEN 家族蛋白的生物功能和分

工机制将为肿瘤和代谢研究开创新的局面。

九、4 月份论文列表

Potent Neutralization of MERS-CoV by Human Neutralizing Monoclonal Antibodies to the

Viral Spike Glycoprotein. [链接]

通讯作者：张林琦&王新泉&郑柏建（清华大学&清华大学&香港大学）Sci Transl Med.

2014Apr 30;6(234):234ra59. doi: 10.1126/scitranslmed.3008140. Epub 2014 Apr 28.

The recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe

and fatal acute respiratory illness in humans. However, no prophylactic and therapeutic agents

specifically against MERS-CoV are currently available. Entry of MERS-CoV into target cells

depends on binding of the receptor binding domain (RBD) of the viral envelope spike

glycoprotein to the cellular receptor dipeptidyl peptidase 4 (DPP4). We report the isolation and

characterization of two potent human RBD-specific neutralizing monoclonal antibodies (MERS-4

and MERS-27) derived from single-chain variable region fragments of a nonimmune human

17

antibody library. MERS-4 and MERS-27 inhibited infection of both pseudotyped and live

MERS-CoV with IC50 (half-maximal inhibitory concentration) at nanomolar concentrations.

MERS-4 also showed inhibitory activity against syncytia formation mediated by interaction

between MERS-CoV spike glycoprotein and DPP4. Combination of MERS-4 and MERS-27

demonstrated a synergistic effect in neutralization against pseudotyped MERS-CoV. Biochemical

analysis indicated that MERS-4 and MERS-27 blocked RBD interaction with DPP4 on the cell

surface. MERS-4, in particular, bound soluble RBD with an about 45-fold higher affinity than

DPP4. Mutagenesis analysis suggested that MERS-4 and MERS-27 recognized distinct regions in

RBD. These results suggest that MERS-4 and MERS-27 are RBD-specific potent inhibitors and

could serve as promising candidates for prophylactic and therapeutic interventions against

MERS-CoV infection.

Heterotrimeric G proteins regulate nitrogen-use efficiency in rice[链接]

通讯作者：傅向东（中国科学院遗传与发育生物学研究所） Nat Genet. 2014 Apr 28. doi:

10.1038/ng.2958.

The drive toward more sustainable agriculture has raised the profile of crop plant nutrient-use

efficiency. Here we show that a major rice nitrogen-use efficiency quantitative trait locus (qNGR9)

is synonymous with the previously identified gene DEP1 (DENSE AND ERECT PANICLES 1).

The different DEP1 alleles confer different nitrogen responses, and genetic diversity analysis

suggests that DEP1 has been subjected to artificial selection during Oryza sativa spp. japonica rice

domestication. The plants carrying the dominant dep1-1 allele exhibit nitrogen-insensitive

vegetative growth coupled with increased nitrogen uptake and assimilation, resulting in improved

harvest index and grain yield at moderate levels of nitrogen fertilization. The DEP1 protein

interacts in vivo with both the Gα (RGA1) and Gβ (RGB1) subunits, and reduced RGA1 or

enhanced RGB1 activity inhibits nitrogen responses. We conclude that the plant G protein

complex regulates nitrogen signaling and modulation of heterotrimeric G protein activity provides

a strategy for environmentally sustainable increases in rice grain yield.

Organizer-derived Bmp2 is required for the formation of a correct Bmp activity gradient

during embryonic development. [链接]

通讯作者：陶毅&孟安明（中国科学院计算与进化生物学研究中心&清华大学、中国科学院

动物研究所）Nat Commun. 2014 Apr 29;5:3766. doi: 10.1038/ncomms4766.

Bone morphogenetic proteins (Bmps) control dorsoventral patterning of vertebrate embryos

through the establishment of a ventrodorsal gradient of the activated downstream cytoplasmic

effectors Smad1/5/8. Some Bmp ligands are expressed in the ventral and lateral regions and in the

organizer during gastrulation of the embryo, but it remains unclear how organizer-derived Bmps

contribute to total Bmp ligand levels and to the establishment of the correct phospho-Smad1/5/8

gradient along the ventrodorsal axis. Here we demonstrate that interference with

organizer-specific Bmp2b signalling in zebrafish embryos alters the phospho-Smad1/5/8 gradient

throughout the ventrodorsal axis, elevates the levels of the Bmp antagonist Chordin and dorsalizes

18

the embryos. Moreover, we show that organizer-derived Bmp2b represses chordin transcription in

the organizer and contributes to the control of the Chordin gradient. Combining these

experimental results with simulations of Bmp's reaction-diffusion dynamics, our data indicate that

organizer-produced Bmp2b is required for the establishment and maintenance of a Bmp activity

gradient and for appropriate embryonic dorsoventral patterning during gastrulation.

K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ubiquitin E3 Ligase

Regulates Protein Trafficking. [链接]

通讯作者：陈瑞华（台湾中央研究院、国立台湾大学）Mol Cell. 2014 Apr 23. pii:

S1097-2765(14)00268-8. doi: 10.1016/j.molcel.2014.03.035.

Ubiquitin chains are formed as structurally distinct polymers via different linkages, and several

chain types including K33-linkage remain uncharacterized. Here, we describe a role for

K33-polyubiquitination in protein trafficking. We show that the Cullin 3 (Cul3) substrate adaptor

KLHL20 is localized to the trans-Golgi network (TGN) and is important for post-Golgi trafficking

by promoting the biogenesis of TGN-derived transport carriers. The Cul3-KLHL20 ubiquitin E3

ligase catalyzes a nondegradable, K33-linked polyubiquitination on coronin 7 (Crn7), which

facilitates Crn7 targeting to TGN through a ubiquitin-dependent interaction with Eps15. Blockage

of K33-chain formation, Crn7 ubiquitination, or disruption of Crn7-Eps15 interaction impairs

TGN-pool F-actin assembly, a process essential for generating transport carriers. Enforced

targeting of Crn7 to TGN bypasses the requirement of K33-ubiquitination for TGN-pool F-actin

assembly and post-Golgi trafficking. Our study reveals a role of KLHL20-mediated

K33-ubiquitination of Crn7 in post-Golgi transport and identifies a cellular recognition

mechanism for this ubiquitin chain type.

PTENα, a PTEN Isoform Translated through Alternative Initiation, Regulates

Mitochondrial Function and Energy Metabolism. [链接]

通 讯 作 者 ： 尹 玉 新 （ 北 京 大 学 ） Cell Metab. 2014 May 6;19(5):836-48. doi:

10.1016/j.cmet.2014.03.023

PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a

wide range of biological functions beyond tumor suppression. Here, we report that PTENα , an

N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of

PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of

canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation,

which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c

oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTEN

α impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to

increase PINK1 protein levels and promote energy production. Our studies demonstrate the

importance of eIF2A-mediated alternative translation for generation of protein diversity in

eukaryotic systems and provide insights into the mechanism by which the PTEN family is

involved in multiple cellular processes.

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Primordial dwarfism gene maintains lin28 expression to safeguard embryonic stem cells

from premature differentiation. [链接]

通 讯 作 者 ： 李 沁 桐 ( 四 川 大 学 )Cell Rep. 2014 May 8;7(3):735-46. doi:

10.1016/j.celrep.2014.03.053.

Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis

and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family,

member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was

previously assumed to be associated with increased cell growth and proliferation via activation of

positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely

does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does

not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via

downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show

that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We

propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a

sufficient number of cell divisions prior to differentiation and ultimately to maintain proper

organismal size.

A Long Noncoding RNA Activated by TGF-β Promotes the Invasion-Metastasis Cascade in

Hepatocellular Carcinoma. [链接]

通讯作者：孙树汉（第二军医大学） Cancer Cell. 2014 May 12;25(5):666-81. doi:

10.1016/j.ccr.2014.03.010.

The role of TGF- β -induced epithelial-mesenchymal transition (EMT) in cancer cell

dissemination is well established, but the involvement of lncRNAs in TGF-β signaling is still

unknown. In this study, we observed that the lncRNA-activated by TGF-β (lncRNA-ATB) was

upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis.

lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and

then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of

disseminated tumor cells by binding IL-11 mRNA, autocrine induction of IL-11, and triggering

STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these

findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose HCC

patients to metastases and may serve as a potential target for antimetastatic therapies.

Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal

units. [链接]

通讯作者：李国红&朱平(中国科学院生物物理研究所) Science. 2014 Apr 25;344(6182):376-80.

doi: 10.1126/science.1251413.

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The hierarchical packaging of eukaryotic chromatin plays a central role in transcriptional

regulation and other DNA-related biological processes. Here, we report the

11-angstrom-resolution cryogenic electron microscopy (cryo-EM) structures of 30-nanometer

chromatin fibers reconstituted in the presence of linker histone H1 and with different nucleosome

repeat lengths. The structures show a histone H1-dependent left-handed twist of the repeating

tetranucleosomal structural units, within which the four nucleosomes zigzag back and forth with a

straight linker DNA. The asymmetric binding and the location of histone H1 in chromatin play a

role in the formation of the 30-nanometer fiber. Our results provide mechanistic insights into how

nucleosomes compact into higher-order chromatin fibers.

Structures and mechanism for the design of highly potent glucocorticoids[链接]

通讯作者：徐华强(中国科学院上海药物研究所)Cell Res. 2014 Apr 25. doi: 10.1038/cr.2014.52

The evolution of glucocorticoid drugs was driven by the demand of lowering the unwanted side

effects, while keeping the beneficial anti-inflammatory effects. Potency is an important aspect of

this evolution as many undesirable side effects are associated with use of high-dose

glucocorticoids. The side effects can be minimized by highly potent glucocorticoids that achieve

the same treatment effects at lower doses. This demand propelled the continuous development of

synthetic glucocorticoids with increased potencies, but the structural basis of their potencies is

poorly understood. To determine the mechanisms underlying potency, we solved the X-ray

structures of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to its

endogenous ligand, cortisol, which has relatively low potency, and a highly potent synthetic

glucocorticoid, mometasone furoate (MF). The cortisol-bound GR LBD revealed that the

flexibility of the C1-C2 single bond in the steroid A ring is primarily responsible for the low

affinity of cortisol to GR. In contrast, we demonstrate that the very high potency of MF is

achieved by its C-17α furoate group completely filling the ligand-binding pocket, thus providing

additional anchor contacts for high-affinity binding. A single amino acid in the ligand-binding

pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol.

Structure-based design led to synthesis of several novel glucocorticoids with much improved

potency and efficacy. Together, these results reveal key structural mechanisms of glucocorticoid

potency and provide a rational basis for developing novel highly potent glucocorticoids.

Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human

colorectal cancer cell lines by cucurbitacin E. [链接]

通讯作者：徐怡強(长荣大学) Cell Death Dis. 2014 Apr 24;5:e1198. doi: 10.1038/cddis.2014.151.

Cucurbitacin E (CuE) or α -elaterin is a natural compound previously shown to be an antifeedant

as well as a potent chemopreventive agent against several types of cancer. The present study

investigated the anticancer effects of CuE on colorectal cancer (CRC) using primary cell lines

isolated from five CRC patients in Taiwan, Specifically, we explored the anti-proliferation and cell

cycle G2/M arrest induced by CuE in CRC cells. MPM-2 flow cytometry tests show that

CuE-treated cells accumulated in metaphase (CuE 2.5-7.5 μ M). Results further indicate that CuE

21

produced G2/M arrest as well as the downregulation of CDC2 and cyclin B1 expression and

dissociation. Both effects increased proportionally with the dose of CuE; however, the inhibition

of proliferation, arrest of mitosis, production of reactive oxygen species (ROS), and loss of

mitochondrial membrane potential (Δ Ψm) were found to be dependent on the quantity of CuE

used to treat the cancer cells. In addition, cell cycle arrest in treated cells coincided with the

activation of the gene GADD45(α , β , γ ). Incubation with CuE resulted in the binding of

GADD45γ to CDC2, which suggests that the delay in CuE-induced mitosis is regulated by the

overexpression of GADD45γ . Our findings suggest that, in addition to the known effects on

cancer prevention, CuE may have antitumor activities in established CRC.

MicroRNA-185 regulates chemotherapeutic sensitivity in gastric cancer by targeting

apoptosis repressor with caspase recruitment domain. [链接]

通讯作者：李培峰(中国科学院动物研究所 )Cell Death Dis. 2014 Apr 24;5:e1197. doi:

10.1038/cddis.2014.148.

Gastric cancer remains the second leading cause of cancer deaths worldwide. Resistance to

chemotherapy is a significant barrier for effective cancer treatment. Here, we identified miR-185

to be a contributor to chemosensitivity in gastric cancer. We observed low levels of miR-185 in

gastric cancer cell lines and clinical tissues, compared with gastric epithelium cell line and

noncancerous tissues. Furthermore, enforced expression of miR-185 increased the sensitivity of

gastric cancer cells to low-dose chemotherapeutic agents, which alone cannot trigger significant

apoptosis. Conversely, knockdown of endogenous miR-185 prevented high-dose

chemotherapy-induced apoptosis. In elucidating the molecular mechanism by which miR-185

participated in the regulation of chemosensitivity in gastric cancer, we discovered that apoptosis

repressor with caspase recruitment domain (ARC) is a direct target of miR-185. The role of

miR-185 was confirmed in gastric tumor xenograft model. The growth of established tumors was

suppressed by a combination therapy using enforced miR-185 expression and a low dose of

anticancer drugs. Finally, we found that RUNX3 (Runt-related transcription factor) was involved

in the activation of miR-185 at the transcriptional level. Taken together, our results reveal that

RUNX3, miR-185 and ARC regulate the sensitivity of gastric cancer cells to chemotherapy.

The histone methyltransferase ESET is required for the survival of spermatogonial

stem/progenitor cells in mice[链接]

通讯作者：曾文先 (西北农林科技大学 )Cell Death Dis. 2014 Apr 24;5:e1196. doi:

10.1038/cddis.2014.171.

Self-renewal and differentiation of spermatogonial stem cells (SSCs) are the foundation of

spermatogenesis throughout a male's life. SSC transplantation will be a valuable solution for

young male patients to preserve their fertility. As SSCs in the collected testis tissue from the

patients are very limited, it is necessary to expansion the SSCs in vitro. Previous studies suggested

that histone methyltransferase ERG-associated protein with SET domain (ESET) represses gene

expression and is essential for the maintenance of the pool of embryonic stem cells and neurons.

22

The objective of this study was to determine the role of ESET in SSCs using in vitro cell culture

and germ cell transplantation. Cell transplantation assay showed that knockdown of ESET reduced

the number of seminiferous tubules with spermatogenesis when compared with that of the control.

Knockdown of ESET also upregulated the expression of apoptosis-associated genes (such as P53,

Caspase9, Apaf1), whereas inhibited the expression of apoptosis-suppressing genes (such as

Bcl2l1, X-linked inhibitor of apoptosis protein). In addition, suppression of ESET led to increase

in expression of Caspase9 and activation of Caspase3 (P17) as well as cleavage of poly

(ADP-ribose) polymerase. Among the five ESET-targeting genes (Cox4i2, spermatogenesis and

oogenesis Specific Basic Helix-Loop-Helix 2, Nobox, Foxn1 and Dazl) examined by ChIP assay,

Cox4i2 was found to regulate SSC apoptosis by the rescue experiment. BSP analyses further

showed that DNA methylation in the promoter loci of Cox4i2 was influenced by ESET, indicating

that ESET also regulated gene expression through DNA methylation in addition to histone

methylation. In conclusion, we found that ESET regulated SSC apoptosis by suppressing of

Cox4i2 expression through histone H3 lysine 9 tri-methylation and DNA methylation. The results

obtained will provide unique insights that would broaden the research on SSC biology and

contribute to the treatment of male infertility.

Grb10 Promotes Lipolysis and Thermogenesis by Phosphorylation-Dependent Feedback

Inhibition of mTORC1[链接]

通讯作者：刘峰(中南大学) Cell Metab. 2014 Apr 15. pii: S1550-4131(14)00123-5. doi:

10.1016/j.cmet.2014.03.018.

Identification of key regulators of lipid metabolism and thermogenic functions has important

therapeutic implications for the current obesity and diabetes epidemic. Here, we show that Grb10,

a direct substrate of mechanistic/mammalian target of rapamycin (mTOR), is expressed highly in

brown adipose tissue, and its expression in white adipose tissue is markedly induced by cold

exposure. In adipocytes, mTOR-mediated phosphorylation at Ser501/503 switches the binding

preference of Grb10 from the insulin receptor to raptor, leading to the dissociation of raptor from

mTOR and downregulation of mTOR complex 1 (mTORC1) signaling. Fat-specific disruption of

Grb10 increased mTORC1 signaling in adipose tissues, suppressed lipolysis, and reduced

thermogenic function. The effects of Grb10 deficiency on lipolysis and thermogenesis were

diminished by rapamycin administration in vivo. Our study has uncovered a unique feedback

mechanism regulating mTORC1 signaling in adipose tissues and identified Grb10 as a key

regulator of adiposity, thermogenesis, and energy expenditure.

Mouse SCNT ESCs Have Lower Somatic Mutation Load Than Syngeneic iPSCs. [链接]

通讯作者：邓宏魁 ( 北京大学 )Stem Cell Reports. 2014 Mar 27;2(4):399-405. doi:

10.1016/j.stemcr.2014.02.005.

Ectopic expression of reprogramming factors has been widely adopted to reprogram somatic

nucleus into a pluripotent state (induced pluripotent stem cells [iPSCs]). However, genetic

aberrations such as somatic gene mutation in the resulting iPSCs have raised concerns regarding

23

their clinical utility. To test whether the increased somatic mutations are primarily the by-products

of current reprogramming methods, we reprogrammed embryonic fibroblasts of inbred C57BL/6

mice into either iPSCs (8 lines, 4 previously published) or embryonic stem cells (ESCs) with

somatic cell nuclear transfer (SCNT ESCs; 11 lines). Exome sequencing of these lines indicates a

significantly lower mutation load in SCNT ESCs than iPSCs of syngeneic background. In addition,

one SCNT-ESC line has no detectable exome mutation, and two pairs of SCNT-ESC lines only

have shared preexisting mutations. In contrast, every iPSC line carries unique mutations. Our

study highlights the need for improving reprogramming methods in more physiologically relevant

conditions.

Impeded nedd4-1-mediated ras degradation underlies ras-driven tumorigenesis. [链接]

通讯作者：王洪睿 & 尹震宇 ( 厦门大学 ) Cell Rep. 2014 May 8;7(3):871-82. doi:

10.1016/j.celrep.2014.03.045.C

RAS genes are among the most frequently mutated proto-oncogenes in cancer. However, how Ras

stability is regulated remains largely unknown. Here, we report a regulatory loop involving the E3

ligase Nedd4-1, Ras, and PTEN. We found that Ras signaling stimulates the expression of

Nedd4-1, which in turn acts as an E3 ubiquitin ligase that regulates Ras levels. Importantly, Ras

activation, either by oncogenic mutations or by epidermal growth factor (EGF) signaling, prevents

Nedd4-1-mediated Ras ubiquitination. This leads to Ras-induced Nedd4-1 overexpression, and

subsequent degradation of the tumor suppressor PTEN in both human cancer samples and cancer

cells. Our study thus unravels the molecular mechanisms underlying the interplay of Ras, Nedd4-1,

and PTEN and suggests a basis for the high prevalence of Ras-activating mutations and EGF

hypersignaling in cancer.

Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3

proteins Bim and Noxa. [链接]

通讯作者：李绍平(澳门大学)Cell Death Dis. 2014 Apr 24;5:e1190. doi: 10.1038/cddis.2014.169.

Oplopantriol-A (OPT) is a natural polyyne from Oplopanax horridus. We show here that OPT

preferentially kills cancer cells and inhibits tumor growth. We demonstrate that OPT-induced

cancer cell death is mediated by excessive endoplasmic reticulum (ER) stress. Decreasing the

level of ER stress either by inactivating components of the unfolded protein response (UPR)

pathway or by expression of ER chaperone protein glucose-regulated protein 78 (GRP78)

decreases OPT-induced cell death. We show that OPT induces the accumulation of ubiquitinated

proteins and the stabilization of unstable proteins, suggesting that OPT functions, at least in part,

through interfering with the ubiquitin/proteasome pathway. In support of this, inhibition of protein

synthesis significantly decreased the accumulation of ubiquitinated proteins, which is correlated

with significantly decreased OPT-induced ER stress and cell death. Finally, we show that OPT

treatment significantly induced the expression of BH3-only proteins, Noxa and Bim. Knockdown

of both Noxa and Bim significantly blocked OPT-induced cell death. Taken together, our results

suggest that OPT is a potential new anticancer agent that induces cancer cell death through

24

inducing ER stress and BH3 proteins Noxa and Bim.

Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural

inhibitor of TrxR1 in vitro and in vivo. [链接]

通讯作者：陈填烽(暨南大学)Cell Death Dis. 2014 Apr 24;5:e1191. doi: 10.1038/cddis.2014.132.

Thioredoxin reductase (TrxR) is overexpressed in many human tumors and has a key role in

regulating intracellular redox balance. Recently, thioredoxin system has emerged as a valuable

target for anticancer drug development. Herein we demonstrate that selenocystine (SeC) could

enhance auranofin (AF)-induced A549 human lung adenocarcinoma cell apoptosis in vitro and in

vivo through synergetic inhibition of TrxR1. SeC pretreatment significantly enhanced AF-induced

loss of mitochondrial membrane potential (Δ ψ m) by regulating Bcl-2 family proteins. The

combined treatment with SeC and AF also resulted in enhanced intracellular reactive oxygen

species (ROS) accumulation, DNA damage, and inactivation of ERK and AKT. Inhibitors of ERK

and AKT effectively enhanced combined treatment-induced apoptotic cell death. However,

inhibition of ROS reversed the apoptosis induced by SeC and AF, and recovered the inactivation

of ERK and AKT, which revealed the importance of ROS in cell apoptosis and regulation of ERK

and AKT pathways. Moreover, xenograft lung tumor growth in nude mice was more effectively

inhibited by combined treatment with SeC and AF by induction of apoptosis through targeting

TrxR1 in vivo. Taken together, our results suggest the strategy to use SeC and AF in combination

could be a highly efficient way to achieve anticancer synergism by targeting TrxR1.

Small GTPase RBJ Mediates Nuclear Entrapment of MEK1/MEK2 in Tumor Progression.

[链接]

通讯作者：曹雪涛(第二军医大学&中国医学科学院基础医学研究所&浙江大学)Cancer Cell.

2014 May 12;25(5):682-96. doi: 10.1016/j.ccr.2014.03.009.

Ras-related small GTPases play important roles in cancer. However, the roles of RBJ, a

representative of the sixth subfamily of Ras-related small GTPases, in tumorigenesis and tumor

progression remain unknown. Here, we report that RBJ is dysregulated in human gastrointestinal

cancers and can promote carcinogenesis and tumor progression via nuclear entrapment of

mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)1/MEK2 and

activation of ERK1/ERK2. Nucleus-localized RBJ interacts with MEK/ERK and prolongs the

duration of MEK/ERK activation. Rbj deficiency abrogates nuclear accumulation of

MEK1/MEK2, attenuates ERK1/ERK2 activation, and impairs AOM/DSS-induced colonic

carcinogenesis. Moreover, Rbj knockdown inhibits growth of established tumors. Our data suggest

that RBJ may be an oncogenic Ras-related small GTPase mediating nuclear accumulation of

active MEK1/MEK2 in tumor progression.

A Regulatory Signaling Loop Comprising the PGAM5 Phosphatase and CK2 Controls

Receptor-Mediated Mitophagy. [链接]

25

通讯作者：陈佺&朱玉山(南开大学、中国科学院动物研究所&南开大学）Mol Cell. 2014 May

8;54(3):362-77. doi: 10.1016/j.molcel.2014.02.034

Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality

control via selectively removing damaged or unwanted mitochondria. Interactions between LC3

and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are

essential for this selective process. However, how mitochondrial stresses are sensed to activate

receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially

localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13)

upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment.

Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is

abrogated following knockdown of PGAM5 or the introduction of a cell-permeable

unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed

that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our

results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the

dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy.

Specificity and promiscuity at the branch point in gentamicin biosynthesis. [链接]

通 讯 作 者 ： 孙 宇 辉 （ 武 汉 大 学 ） Chem Biol. 2014 May 22;21(5):608-18. doi:

10.1016/j.chembiol.2014.03.005.

Gentamicin C complex is a mixture of aminoglycoside antibiotics used to treat severe

Gram-negative bacterial infections. We report here key features of the late-stage biosynthesis of

gentamicins. We show that the intermediate gentamicin X2, a known substrate for C-methylation

at C-6' to form G418 catalyzed by the radical SAM-dependent enzyme GenK, may instead

undergo oxidation at C-6' to form an aldehyde, catalyzed by the flavin-linked dehydrogenase

GenQ. Surprisingly, GenQ acts in both branches of the pathway, likewise oxidizing G418 to an

analogous ketone. Amination of these intermediates, catalyzed mainly by aminotransferase GenB1,

produces the known intermediates JI-20A and JI-20B, respectively. Other pyridoxal

phosphate-dependent enzymes (GenB3 and GenB4) act in enigmatic dehydroxylation steps that

convert JI-20A and JI-20B into the gentamicin C complex or (GenB2) catalyze the epimerization

of gentamicin C2a into gentamicin C2.

Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on

Runx2 to regulate BMP-2-induced osteoblastic differentiation. [链接]

通讯作者：邹刚明&李青峰（上海交通大学）Cell Death Dis. 2014 Apr 17;5:e1187. doi:

10.1038/cddis.2014.101.

In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels

of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated,

which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK)

cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal

26

kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both

BMP-2 and TNF-α /IL-1β . However, previous studies suggested that the effects of BMP-2 and

TNF-α /IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of

MAPKs in a BMP-2 and TNF-α /IL-1β co-existed condition. Treatment with TNF-α /IL-1β

inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic

transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1

cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the

presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent

osteoblastic differentiation. We then confirmed that BMP-2, TNF-α , and IL-1β alone can

activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2

signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined

that TNF-α /IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38

and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by

transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and

osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude

that TNF-α /IL-1β - and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that

converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms

may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2

in the clinic to enhance osteoblastic differentiation and bone formation.

The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell

differentiation. [链接]

通讯作者：曹雪涛（第二军医大学&中国医学科学院基础医学研究所&浙江大学）Science.

2014 Apr 18;344(6181):310-3. doi: 10.1126/science.1251456.

Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however,

few have been identified that regulate immune cell differentiation and function. Here, we

identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs).

Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from

mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation.

lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and

activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted

STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation

by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the

known mechanisms of lncRNA action.

Selective 14-3-3γ induction quenches p-β-catenin Ser37/Bax-enhanced cell death in cerebral

cortical neurons during ischemia[链接]

通讯作者：陈晓钎（华中科技大学） Cell Death Dis. 2014 Apr 17;5:e1184. doi:

10.1038/cddis.2014.152.

Ischemia-induced cell death is a major cause of disability or death after stroke. Identifying the key

27

intrinsic protective mechanisms induced by ischemia is critical for the development of effective

stroke treatment. Here, we reported that 14-3-3γ was a selective ischemia-inducible survival

factor in cerebral cortical neurons reducing cell death by downregulating Bax depend direct

14-3-3γ /p-β -catenin Ser37 interactions in the nucleus. 14-3-3γ , but not other 14-3-3 isoforms,

was upregulated in primary cerebral cortical neurons upon oxygen-glucose deprivation (OGD) as

measured by quantitative PCR, western blot and fluorescent immunostaining. The selective

induction of 14-3-3γ in cortical neurons by OGD was verified by the in vivo ischemic stroke

model. Knocking down 14-3-3γ alone or inhibiting 14-3-3/client interactions was sufficient to

induce cell death in normal cultured neurons and exacerbate OGD-induced neuronal death.

Ectopic overexpression of 14-3-3γ significantly reduced OGD-induced cell death in cultured

neurons. Co-immunoprecipitation and fluorescence resonance energy transfer demonstrated that

endogenous 14-3-3γ bound directly to more p-β -catenin Ser37 but not p-Bad, p-Ask-1, p-p53

and Bax. During OGD, p-β -catenin Ser37 but not p-β -catenin Ser45 was increased prominently,

which correlated with Bax elevation in cortical neurons. OGD promoted the entry of 14-3-3γ

into the nuclei, in correlation with the increase of nuclear p-β -catenin Ser37 in neurons.

Overexpression of 14-3-3γ significantly reduced Bax expression, whereas knockdown of 14-3-3

γ increased Bax in cortical neurons. Abolishing β -catenin phosphorylation at Ser37 (S37A)

significantly reduced Bax and cell death in neurons upon OGD. Finally, 14-3-3γ overexpression

completely suppressed β -catenin-enhanced Bax and cell death in neurons upon OGD. Based on

these data, we propose that the 14-3-3γ /p-β -catenin Ser37/Bax axis determines cell survival or

death of neurons during ischemia, providing novel therapeutic targets for ischemic stroke as well

as other related neurological diseases.

TRPV1 activation impedes foam cell formation by inducing autophagy in oxLDL-treated

vascular smooth muscle cells. [链接]

通讯作者：张莉莉&李敬诚（第三军医大学）Cell Death Dis. 2014 Apr 17;5:e1182. doi:

10.1038/cddis.2014.146.

Vascular smooth muscle cells (VSMCs) are an important origin of foam cells besides

macrophages. The mechanisms underlying VSMC foam cell formation are relatively little known.

Activation of transient receptor potential vanilloid subfamily 1 (TRPV1) and autophagy have a

potential role in regulating foam cell formation. Our study demonstrated that autophagy protected

against foam cell formation in oxidized low-density lipoprotein (oxLDL)-treated VSMCs;

activation of TRPV1 by capsaicin rescued the autophagy impaired by oxLDL and activated

autophagy-lysosome pathway in VSMCs; activation of TRPV1 by capsaicin impeded foam cell

formation of VSMCs through autophagy induction; activation of TRPV1 by capsaicin induced

autophagy through AMP-activated protein kinase (AMPK) signaling pathway. This study provides

evidence that autophagy plays an important role in VSMC foam cell formation and highlights

TRPV1 as a promising therapeutic target in atherosclerosis.

Synergistic effects of glycated chitosan with high-intensity focused ultrasound on

suppression of metastases in a syngeneic breast tumor model. [链接]

28

通讯作者：李易展（国立阳明大学） Cell Death Dis. 2014 Apr 17;5:e1178. doi:

10.1038/cddis.2014.159.

Stimulation of the host immune system is crucial in cancer treatment. In particular, nonspecific

immunotherapies, when combined with other traditional therapies such as radiation and

chemotherapy, may induce immunity against primary and metastatic tumors. In this study, we

demonstrate that a novel, non-toxic immunoadjuvant, glycated chitosan (GC), decreases the

motility and invasion of mammalian breast cancer cells in vitro and in vivo. Lung metastatic ratios

were reduced in 4T1 tumor-bearing mice when intratumoral GC injection was combined with

local high-intensity focused ultrasound (HIFU) treatment. We postulate that this treatment

modality stimulates the host immune system to combat cancer cells, as macrophage accumulation

in tumor lesions was detected after GC-HIFU treatment. In addition, plasma collected from

GC-HIFU-treated tumor-bearing mice exhibited tumor-specific cytotoxicity. We also investigated

the effect of GC on epithelial-mesenchymal transition-related markers. Our results showed that

GC decreased the expression of Twist-1 and Slug, proto-oncogenes commonly implicated in

metastasis. Epithelial-cadherin, which is regulated by these genes, was also upregulated. Taken

together, our current data suggest that GC alone can reduce cancer cell motility and invasion,

whereas GC-HIFU treatment can induce immune responses to suppress tumor metastasis in vivo.

Salt-inducible kinase 3 is a novel mitotic regulator and a target for enhancing antimitotic

therapeutic-mediated cell death. [链接]

通讯作者：潘逸才（香港科技大学） Cell Death Dis. 2014 Apr 17;5:e1177. doi:

10.1038/cddis.2014.154.

Many mitotic kinases are both critical for maintaining genome stability and are important targets

for anticancer therapies. We provide evidence that SIK3 (salt-inducible kinase 3), an

AMP-activated protein kinase-related kinase, is important for mitosis to occur properly in

mammalian cells. Downregulation of SIK3 resulted in an extension of mitosis in both mouse and

human cells but did not affect the DNA damage checkpoint. Time-lapse microscopy and other

approaches indicated that mitotic exit but not mitotic entry was delayed. Although repression of

SIK3 alone simply delayed mitotic exit, it was able to sensitize cells to various antimitotic

chemicals. Both mitotic arrest and cell death caused by spindle poisons were enhanced after SIK3

depletion. Likewise, the antimitotic effects due to pharmacological inhibition of mitotic kinases

including Aurora A, Aurora B, and polo-like kinase 1 were enhanced in the absence of SIK3.

Finally, in addition to promoting the sensitivity of a small-molecule inhibitor of the mitotic kinesin

Eg5, SIK3 depletion was able to overcome cells that developed drug resistance. These results

establish the importance of SIK3 as a mitotic regulator and underscore the potential of SIK3 as a

druggable antimitotic target.

Sublytic C5b-9 triggers glomerular mesangial cell apoptosis via XAF1 gene activation

mediated by p300-dependent IRF-1 acetylation. [链接]

通讯作者：王迎伟（南京医科大学） Cell Death Dis. 2014 Apr 17;5:e1176. doi:

29

10.1038/cddis.2014.153.

The apoptosis of glomerular mesangial cells (GMCs) in rat Thy-1 nephritis (Thy-1N), a model of

human mesangioproliferative glomerulonephritis (MsPGN), is accompanied by sublytic C5b-9

deposition. However, the mechanism by which sublytic C5b-9 induces GMC apoptosis is unclear.

In the present studies, the effect of X-linked inhibitor of apoptosis-associated factor 1 (XAF1)

expression on GMC apoptosis and the role of p300 and interferon regulatory factor-1 (IRF-1) in

mediating XAF1 gene activation were determined, both in the GMCs induced by sublytic C5b-9

(in vitro) and in the renal tissues of rats with Thy-1N (in vivo). The in vitro studies demonstrated

that IRF-1-enhanced XAF1 gene activation and its regulation by p300-mediated IRF-1 acetylation

were involved in GMC apoptosis induced by sublytic C5b-9. The element of IRF-1 binding to

XAF1 promoter and two acetylated sites of IRF-1 protein were also revealed. In vivo, silence of

p300, IRF-1 or XAF1 genes in the renal tissues diminished GMC apoptosis and secondary GMC

proliferation as well as urinary protein secretion in Thy-1N rats. Together, these data implicate that

sublytic C5b-9 induces the expression of both p300 and IRF-1, as well as p300-dependent IRF-1

acetylation that may contribute to XAF1 gene activation and subsequent GMC apoptosis in

Thy-1N rats.

Synthesis, labeling and bioanalytical applications of a

tris(2,2'-bipyridyl)ruthenium(II)-based electrochemiluminescence probe. [链接]

通 讯 作 者 ： 邢 达 （ 华 南 师 范 大 学 ） Nat Protoc. 2014 May;9(5):1146-59. doi:

10.1038/nprot.2014.060.

Assays using probes labeled with electrochemiluminescent moieties are extremely powerful

analytical tools that are used in fields such as medical diagnostics, environmental analysis and

food safety monitoring, in which sensitive, reliable and reproducible detection of biomolecules is

a requirement. The most efficient electrochemiluminescence (ECL) reaction to date is based on

tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)3(2+)) with tripropylamine (TPrA) as the co-reactant.

Here we present a detailed protocol for preparing Ru(bpy)3(2+) probes and their bioanalytical

applications. This protocol includes (i) the synthesis of a biologically active

Ru(bpy)3(2+)-N-hydroxysuccinimide (NHS) ester, (ii) its covalent labeling with both antibodies

and DNA probes and (iii) the detection and quantification of ECL in a microfluidic system with a

paramagnetic microbead solid support. In our magnetic bead-based ECL system, two probes are

required: a capture probe (labeled with biotin to be captured by a streptavidin-coated magnetic

bead) and a detector probe (labeled with Ru(bpy)3(2+)). The complex consisting of the analyte,

the capture probe, the detector probe and the magnetic bead is brought into contact with the

electrode by using a magnetic field. The Ru(bpy)3(2+) reacts with TPrA in solution to generate the

ECL signal. The full protocol, including the synthesis and labeling of the bioactive Ru(bpy)3(2+),

requires 5-6 d to complete. ECL immunoassays or nucleic acid tests only require 1.5-2 h,

including the sample preparation time.

IKKα restoration via EZH2 suppression induces nasopharyngeal carcinoma

differentiation[链接]

30

通讯作者：刘强（中山大学、大连医科大学）Nat Commun. 2014 Apr 17;5:3661. doi:

10.1038/ncomms4661.

Lack of cellular differentiation is a key feature of nasopharyngeal carcinoma (NPC), but it also

presents as a unique opportunity for intervention by differentiation therapy. Here using RNA-seq

profiling analysis and functional assays, we demonstrate that reduced IKKα expression is

responsible for the undifferentiated phenotype of NPC. Conversely, overexpression of IKKα

induces differentiation and reduces tumorigenicity of NPC cells without activating NF-κ B

signalling. Importantly, we describe a mechanism whereby EZH2 directs IKKα transcriptional

repression via H3K27 histone methylation on the IKKα promoter. The differentiation agent,

retinoic acid, increases IKKα expression by suppressing EZH2-mediated H3K27 histone

methylation, resulting in enhanced differentiation of NPC cells. In agreement, an inverse

correlation between IKKα (low) and EZH2 (high) expression is associated with a lack of

differentiation in NPC patient samples. Collectively, these findings demonstrate a role for IKKα

in NPC differentiation and reveal an epigenetic mechanism for IKKα regulation, unveiling a

new avenue for differentiation therapy.

Involvement of miR-605 and miR-34a in the DNA damage response promotes apoptosis

induction. [链接]

通讯作者：刘锋&王炜（南京大学） Biophys J. 2014 Apr 15;106(8):1792-800. doi:

10.1016/j.bpj.2014.02.032.

MicroRNAs are key regulators of gene expression at the posttranscriptional level. In this study, we

focus on miR-605 and miR-34a, which are direct transcriptional targets of p53 and in turn enhance

its tumor suppressor function by acting upstream and downstream of it, respectively. miR-605

promotes p53 activation by repressing the expression of mdm2, whereas miR-34a promotes

p53-dependent apoptosis by suppressing the expression of antiapoptotic genes such as bcl-2. What

roles they play in the p53-mediated DNA damage response is less well understood. Here, we

develop a four-module model of the p53 network to investigate the effect of miR-605 and

miR-34a on the cell-fate decision after ionizing radiation. Results of numerical simulation indicate

that the cell fate is closely associated with network dynamics. The concentration of p53 undergoes

few pulses in response to repairable DNA damage, or it first oscillates and then switches to high

plateau levels after irreparable damage. The amplitude of p53 pulses rises to various extents

depending on miR-605 expression, and miR-605 accelerates the switching behavior of p53 levels

to induce apoptosis. In parallel, miR-34a promotes apoptosis by enhancing the accumulation of

free p53AIP1, a key proapoptotic protein. Thus, both miR-605 and miR-34a can mediate cellular

outcomes and the timing of apoptosis. Moreover, miR-605 and PTEN complement each other in

elevating p53 levels to trigger apoptosis. Taken together, miR-605 and miR-34a cooperate to

endow the network with a fail-safe mechanism for apoptosis induction. This computational study

also enriches our understanding of the action modes of p53-targeted microRNAs.

Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin

31

silencing[链接]

通 讯 作 者 ： 刘 林 （ 南 开 大 学 ） Dev Cell. 2014 Apr 14;29(1):7-19. doi:

10.1016/j.devcel.2014.03.004.

Telomere length homeostasis is essential for genomic stability and unlimited self-renewal of

embryonic stem cells (ESCs). We show that telomere-associated protein Rif1 is required to

maintain telomere length homeostasis by negatively regulating Zscan4 expression, a critical factor

for telomere elongation by recombination. Depletion of Rif1 results in terminal

hyperrecombination, telomere length heterogeneity, and chromosomal fusions. Reduction of

Zscan4 by shRNA significantly rescues telomere recombination defects of Rif1-depleted ESCs

and associated embryonic lethality. Further, Rif1 negatively modulates Zscan4 expression by

maintaining H3K9me3 levels at subtelomeric regions. Mechanistically, Rif1 interacts and

stabilizes H3K9 methylation complex. Thus, Rif1 regulates telomere length homeostasis of ESCs

by mediating heterochromatic silencing.

Chemerin aggravates DSS-induced colitis by suppressing M2 macrophage polarization[链

接]

通讯作者：何睿（复旦大学）Cell Mol Immunol. 2014 Apr 14. doi: 10.1038/cmi.2014.15.

Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation.

Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or

pro-inflammatory effects according to the disease model being investigated. Elevated circulating

chemerin was recently found in patients with inflammatory bowel disease (IBD); however, the

role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that

the administration of exogenous chemerin (aa17-156) aggravated the severity of dextran sulfate

sodium (DSS)-induced colitis, which was characterized by higher clinical scores, extensive

mucosal damage and significantly increased local and systemic production of pro-inflammatory

cytokines, including IL-6, TNF-α and interferon (IFN-γ ). Interestingly, chemerin did not appear

to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly

decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 (Arg-1),

Ym1, FIZZ1 and IL-10, following DSS exposure, suggesting an impaired M2 macrophage

skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin

directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in

IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from

DSS-exposed mice and from ulcerative colitis (UC) patients and appeared to positively correlate

with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody

significantly improved intestinal inflammation following DSS exposure. Taken together, our

findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of

chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests

that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.

Recruitment of phosphatase PP2A by RACK1 adaptor protein deactivates transcription

32

factor IRF3 and limits type I interferon signaling[链接]

通讯作者：谢东（中国科学院上海生命科学研究院）Immunity. 2014 Apr 17;40(4):515-29. doi:

10.1016/j.immuni.2014.01.015

The transcription factor IRF3 is a central regulator of type I interferon (IFN) signaling. The

mechanisms underlying deactivation of IRF3 are poorly understood although many studies

suggest that IRF3 activity is terminated through degradation after viral infection. Here we report

that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase

PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3

pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. After challenge with

LPS, poly(I:C), or low-titer SeV, activated IRF3 was dephosphorylated and returned to resting

state without being degraded, although high-titer SeV infection triggered the degradation of IRF3.

Furthermore, PP2A-deficient macrophages showed enhanced type I IFN signaling upon LPS,

poly(I:C), and SeV challenge and protected mice from lethal vesicular stomatitis virus infection.

Therefore, dephosphorylation of IRF3 is a deactivation mechanism that contributes to termination

of IRF3-type I IFN signaling.

The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site

Stability[链接]

通讯作者：张令强（军事医学科学院放射与辐射医学研究所、大连医科大学）Cell Rep. 2014

Apr 24;7(2):575-87. doi: 10.1016/j.celrep.2014.03.030.

Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome

replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in

cancer and other human diseases. Despite their importance, the molecular mechanisms that control

human genome stability are incompletely understood. Here, we report a pathway that is required

for human genome replication and stability. This pathway has three components: an E3 ubiquitin

ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6

ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively

regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking

RBBP6 experience reduced replication fork progression and increased damage at common fragile

sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway

that ensures genome-wide DNA replication and chromosomal stability.

An Rrp6-like Protein Positively Regulates Noncoding RNA Levels and DNA Methylation in

Arabidopsis[链接]

通讯作者：朱健康（中国科学院上海生命科学研究院）Mol Cell. 2014 May 8;54(3):418-30. doi:

10.1016/j.molcel.2014.03.019

Rrp6-mediated nuclear RNA surveillance tunes eukaryotic transcriptomes through noncoding

RNA degradation and mRNA quality control, including exosomal RNA decay and transcript

33

retention triggered by defective RNA processing. It is unclear whether Rrp6 can positively

regulate noncoding RNAs and whether RNA retention occurs in normal cells. Here we report that

AtRRP6L1, an Arabidopsis Rrp6-like protein, controls RNA-directed DNA methylation through

positive regulation of noncoding RNAs. Discovered in a forward genetic screen, AtRRP6L1

mutations decrease DNA methylation independently of exosomal RNA degradation. Accumulation

of Pol V-transcribed scaffold RNAs requires AtRRP6L1 that binds to RNAs in vitro and in vivo.

AtRRP6L1 helps retain Pol V-transcribed RNAs in chromatin to enable their scaffold function. In

addition, AtRRP6L1 is required for genome-wide Pol IV-dependent siRNA production that may

involve retention of Pol IV transcripts. Our results suggest that AtRRP6L1 functions in epigenetic

regulation by helping with the retention of noncoding RNAs in normal cells.

Structural Determinants for the Strict Monomethylation Activity by Trypanosoma brucei

Protein Arginine Methyltransferase 7[链接]

通讯作者：施蕴渝&吴季辉（中国科学技术大学&中国科学技术大学）Structure. 2014 May

6;22(5):756-68. doi: 10.1016/j.str.2014.03.003

Trypanosoma brucei protein arginine methyltransferase 7 (TbPRMT7) exclusively generates

monomethylarginine (MMA), which directs biological consequences distinct from that of

symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). However,

determinants controlling the strict monomethylation activity are unknown. We present the crystal

structure of the TbPRMT7 active core in complex with S-adenosyl-L-homocysteine (AdoHcy) and

a histone H4 peptide substrate. In the active site, residues E172, E181, and Q329 hydrogen bond

the guanidino group of the target arginine and align the terminal guanidino nitrogen in a position

suitable for nucleophilic attack on the methyl group of S-adenosyl-L-methionine (AdoMet).

Structural comparisons and isothermal titration calorimetry data suggest that the TbPRMT7 active

site is narrower than those of protein arginine dimethyltransferases, making it unsuitable to bind

MMA in a manner that would support a second turnover, thus abolishing the production of SDMA

and ADMA. Our results present the structural interpretations for the monomethylation activity of

TbPRMT7.

Hydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via

Regulation of Ca2+ Channel Sulfhydration. [链接]

通讯作者：刘谊（首都医科大学）Cell Stem Cell. 2014 Apr 8. pii: S1934-5909(14)00099-X. doi:

10.1016/j.stem.2014.03.005

Gaseous signaling molecules such as hydrogen sulfide (H2S) are produced endogenously and

mediate effects through diverse mechanisms. H2S is one such gasotransmitters that regulates

multiple signaling pathways in mammalian cells, and abnormal H2S metabolism has been linked

to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells

(BMMSCs) produce H2S in order to regulate their self-renewal and osteogenic differentiation, and

H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant

intracellular Ca2+ influx because of reduced sulfhydration of cysteine residues on multiple Ca2+

34

TRP channels. This decreased Ca2+ flux downregulates PKC/Erk-mediated Wnt/β -catenin

signaling which controls osteogenic differentiation of BMMSCs. Consistently, H2S-deficient mice

display an osteoporotic phenotype that can be rescued by small molecules that release H2S. These

results demonstrate that H2S regulates BMMSCs and that restoring H2S levels via nontoxic

donors may provide treatments for diseases such as osteoporosis that can arise from H2S

deficiencies.

Postsynaptic scaffold protein Homer 1a protects against traumatic brain injury via

regulating group I metabotropic glutamate receptors. [链接]

通 讯 作 者 ： 费 舟 （ 第 四 军 医 大 学 ） Cell Death Dis. 2014 Apr 10;5:e1174. doi:

10.1038/cddis.2014.116.

Traumatic brain injury (TBI) produces excessive glutamate, leading to excitotoxicity via the

activation of glutamate receptors. Postsynaptic density scaffold proteins have crucial roles in

mediating signal transduction from glutamate receptors to their downstream mediators. Therefore,

studies on the mechanisms underlying regulation of excitotoxicity by scaffold proteins can

uncover new treatments for TBI. Here, we demonstrated that the postsynaptic scaffold protein

Homer 1a was neuroprotective against TBI in vitro and in vivo, and this neuroprotection was

associated with its effects on group I metabotropic glutamate receptors (mGluRs). Upon further

study, we found that Homer 1a mainly affected neuronal injury induced by mGluR1 activation

after TBI and also influenced mGluR5 function when its activity was restored. The ability of

Homer 1a to disrupt mGluR-ERK signaling contributed to its ability to regulate the functions of

mGluR1 and mGluR5 after traumatic injury. Intracellular Ca(2+) and PKC were two important

factors involved in the mediation of mGluR-ERK signaling by Homer 1a. These results define

Homer 1a as a novel endogenous neuroprotective agent against TBI.

Cardiac hypertrophy is negatively regulated by miR-541[链接]

通讯作者：王昆&李培峰（中国科学院动物研究所）Cell Death Dis. 2014 Apr 10;5:e1171. doi:

10.1038/cddis.2014.141.

Heart failure is a leading cause of death in aging population. Cardiac hypertrophy is an adaptive

reaction of the heart against cardiac overloading, but continuous cardiac hypertrophy is able to

induce heart failure. We found that the level of miR-541 was decreased in angiotensin II (Ang-II)

treated cardiomyocytes. Enforced expression of miR-541 resulted in a reduced hypertrophic

phenotype upon Ang-II treatment in cellular models. In addition, we generated miR-541

transgenic mice that exhibited a reduced hypertrophic response upon Ang-II treatment.

Furthermore, we found miR-541 is the target of microphthalmia-associated transcription factor

(MITF) in the hypertrophic pathway and MITF can negatively regulate the expression of miR-541

at the transcriptional levels. MITF(ce/ce) mice exhibited a reduced hypertrophic phenotype upon

Ang-II treatment. Knockdown of MITF also results in a reduction of hypertrophic responses after

Ang-II treatment. Knockdown of miR-541 can block the antihypertrophic effect of MITF

knockdown in cardiomyocytes upon Ang-II treatment. This indicates that the effect of MITF on

35

cardiac hypertrophy relies on the regulation of miR-541. Our present study reveals a novel cardiac

hypertrophy regulating pathway that was composed of miR-541 and MITF. Modulation of their

levels may provide a new approach for tackling cardiac hypertrophy.

Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer[链接]

通讯作者：张荣信（天津医科大学） Cell Death Dis. 2014 Apr 10;5:e1170. doi:

10.1038/cddis.2014.137

Dysregulated Notch signaling has a critical role in the tumorigenesis. Jagged1, a Notch ligand, is

overexpressed in various human cancers. Recent studies revealed the involvement of Jagged1 in

colorectal cancer (CRC) development. These basic studies provide a promising potential for

inhibition of the Notch pathway for the treatment of CRC. Herein, we aimed to investigate the

consequences of targeting Jagged1 using shRNA on CRC both in vitro and in vivo to test their

potential to inhibit this key element for CRC treatment. We found that downregulation of Jagged1

with lentiviral Jagged1-shRNA resulted in decreased colon cancer cell viability in vitro, most

likely mediated through reduced cell proliferation. Importantly, Jagged1 knockdown induced

G0/G1 phase cell cycle arrest, with reduced Cyclin D1, Cyclin E and c-Myc expression. Silencing

of Jagged1 reduced the migration and invasive capacity of the colon cancer cells in vitro.

Furthermore, colon cancer cells with knockdown of Jagged1 had much slower growth rate than

control cells in a xenograft mouse model in vivo, with a marked downregulation of cell

proliferation markers (PCNA, Ki-67, and c-Myc) and metastasis markers (MMP-2 and MMP-9).

These findings rationalize a mechanistic approach to CRC treatment based on Jagged1-targeted

therapeutic development.

Preclinical anti-arthritic study and pharmacokinetic properties of a potent histone

deacetylase inhibitor MPT0G009. [链接]

通讯作者：杨家荣（国立台湾大学） Cell Death Dis. 2014 Apr 10;5:e1166. doi:

10.1038/cddis.2014.133.

The pathology of rheumatoid arthritis includes synoviocyte proliferation and inflammatory

mediator expression, which may result from dysregulated epigenetic control by histone

deacetylase (HDAC). Thus, HDAC inhibitors may be useful for treating inflammatory disease.

This was a preclinical study of the HDAC inhibitor, MPT0G009. The IC50 values of MPT0G009

for HDAC1, 2, 3, 6 and 8 enzymatic activities were significantly lower than those for the currently

marketed HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat). In addition,

MPT0G009 markedly inhibited cytokine secretion and macrophage colony-stimulating

factor/receptor activator of nuclear factor kappa B ligand-induced osteoclastogenesis by

macrophages (50 ng/ml each). These MPT0G009 effects on cytokine secretion and osteoclast

formation were reduced by the overexpression of HDAC 1 (class I HDAC) and 6 (class II HDAC)

in cells, suggesting that these effects were due to the inhibition of its activity. In an in vivo rat

model, oral administration of MPT0G009 (25 mg/kg) significantly inhibited paw swelling and

bone destruction. Furthermore, compared with SAHA, MPT0G009 exhibited longer half-life (9.53

36

h for oral administration) and higher oral bioavailability (13%) in rats. These results established

the preclinical anti-arthritic efficacy and pharmacokinetic parameters of MPT0G009, which may

provide a new therapeutic approach for treating inflammatory arthritis.

Selective inhibition of protein kinase C β2 attenuates the adaptor P66 Shc-mediated

intestinal ischemia-reperfusion injury. [链接]

通讯作者：姚继红&田晓峰（大连医科大学） Cell Death Dis. 2014 Apr 10;5:e1164. doi:

10.1038/cddis.2014.131.

Apoptosis is a major mode of cell death occurring during ischemia-reperfusion (I/R) induced

injury. The p66(Shc) adaptor protein, which is mediated by PKCβ , has an essential role in

apoptosis under oxidative stress. This study aimed to investigate the role of PKCβ 2/p66(Shc)

pathway in intestinal I/R injury. In vivo, ischemia was induced by superior mesenteric artery

occlusion in mice. Ruboxistaurin (PKCβ inhibitor) or normal saline was administered before

ischemia. Then blood and gut tissues were collected after reperfusion for various measurements.

In vitro, Caco-2 cells were challenged with hypoxia-reoxygenation (H/R) to simulate intestinal I/R.

Translocation and activation of PKC β 2 were markedly induced in the I/R intestine.

Ruboxistaurin significantly attenuated gut damage and decreased the serum levels of tumor

necrosis factor-α (TNF-α ) and interleukin-6 (IL-6). Pharmacological blockade of PKCβ 2

suppressed p66(Shc) overexpression and phosphorylation in the I/R intestine. Gene knockdown of

PKCβ 2 via small interfering RNA (siRNA) inhibited H/R-induced p66(Shc) overexpression and

phosphorylation in Caco-2 cells. Phorbol 12-myristate 13-acetate (PMA), which stimulates PKCs,

induced p66(Shc) phosphorylation and this was inhibited by ruboxistaurin and PKCβ 2 siRNA.

Ruboxistaurin attenuated gut oxidative stress after I/R by suppressing the decreased expression of

manganese superoxide dismutase (MnSOD), the exhaustion of the glutathione (GSH) system, and

the overproduction of malondialdehyde (MDA). As a consequence, ruboxistaurin inhibited

intestinal mucosa apoptosis after I/R. Therefore, PKCβ 2 inhibition protects mice from gut I/R

injury by suppressing the adaptor p66(Shc)-mediated oxidative stress and subsequent apoptosis.

This may represent a novel therapeutic approach for the prevention of intestinal I/R injury.

Orally active microtubule-targeting agent, MPT0B271, for the treatment of human

non-small cell lung cancer, alone and in combination with erlotinib. [链接]

通讯作者：潘秀玲（台北医学大学） Cell Death Dis. 2014 Apr 10;5:e1162. doi:

10.1038/cddis.2014.128.

Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of

cancer. The limitations of these treatments, such as resistance to therapy and the need for

intravenous administration, have encouraged the development of new agents. MPT0B271

(N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally

active microtubule-targeting agent, is a completely synthetic compound that possesses potent

anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence

experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and

37

cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in

numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES.

Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as

determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein

acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest,

accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases

polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15

Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1

denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis

in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1

and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP).

Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly

inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib

treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new

tubulin-binding compound for the treatment of various cancers.

High-throughput screening of a CRISPR/Cas9 library for functional genomics in human

cells. [链接]

通讯作者：魏文胜（北京大学）Nature. 2014 May 22;509(7501):487-91. doi: 10.1038/nature13166

Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis

or loss of ribosomal components are collectively described as 'ribosomopathies'. Treacher Collins

syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is

attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous

studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of

Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in

the early embryo. Here, we established a C. elegans model for studying Nopp140-associated

ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in

gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in

dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on

analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy

on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4

(H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter

were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C.

elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional

upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5

mutant of C. elegans can be a valuable model for studying human Nopp140-associated

ribosomopathy at the cellular and molecular levels.

MicroRNA-181a-mediated downregulation of AC9 protein decreases intracellular cAMP

level and inhibits ATRA-induced APL cell differentiation. [链接]

通讯作者：童建华（上海交通大学） Cell Death Dis. 2014 Apr 10;5:e1161. doi:

38

10.1038/cddis.2014.130.

AC9 is one of the adenylate cyclase (AC) isoforms, which catalyze the conversion of ATP to

cAMP, an important second messenger. We previously found that the integration of cAMP/PKA

pathway with nuclear receptor-mediated signaling was required during all-trans retinoic acid

(ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells. Here we showed that

AC9 could affect intracellular cAMP level and enhance the trans-activity of retinoic acid receptor.

Knockdown of AC9 in APL cell line NB4 could obviously inhibit ATRA-induced differentiation.

We also demonstrated that miR-181a could decrease AC9 expression by targeting 3'UTR of AC9

mRNA, finally controlling the production of intracellular cAMP. The expression of miR-181a

itself could be inhibited by CEBPα , probably accounting for the differential expression of

miR-181a in NB4 and ATRA-resistant NB4-R1 cells. Moreover, we found that AC9 expression

was relatively lower in newly diagnosed or relapsed APL patients than in both complete remission

and non-leukemia cases, closely correlating with the leukemogenesis of APL. Taken together, our

studies revealed for the first time the importance of miR-181a-mediated AC9 downregulation in

APL. We also suggested the potential value of AC9 as a biomarker in the clinical diagnosis and

treatment of leukemia.

Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell

apoptosis in C. elegans. [链接]

通讯作者：罗时成（台湾长庚大学） Cell Death Dis. 2014 Apr 10;5:e1158. doi:

10.1038/cddis.2014.114.

Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis

or loss of ribosomal components are collectively described as 'ribosomopathies'. Treacher Collins

syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is

attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous

studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of

Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in

the early embryo. Here, we established a C. elegans model for studying Nopp140-associated

ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in

gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in

dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on

analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy

on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4

(H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter

were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C.

elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional

upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5

mutant of C. elegans can be a valuable model for studying human Nopp140-associated

ribosomopathy at the cellular and molecular levels.

Downregulation of FAP suppresses cell proliferation and metastasis through

39

PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. [链接]

通讯作者：方唯意&吕晓智（南方医科大学）Cell Death Dis. 2014 Apr 10;5:e1155. doi:

10.1038/cddis.2014.122.

It is largely recognized that fibroblast activation protein (FAP) is expressed in cancer-associated

fibroblasts (CAFs) of many human carcinomas. Furthermore, FAP was recently also reported to be

expressed in carcinoma cells of the breast, stomach, pancreatic ductal adenocarcinoma,

colorectum, and uterine cervix. The carcinoma cell expression pattern of FAP has been described

in several types of cancers, but the role of FAP in oral squamous cell carcinoma (OSCC) is

unknown. The role of endogenous FAP in epithelium-derived tumors and molecular mechanisms

has also not been reported. In this study, FAP was found to be expressed in carcinoma cells of

OSCC and was upregulated in OSCC tissue samples compared with benign tissue samples using

immunohistochemistry. In addition, its expression level was closely correlated with overall

survival of patients with OSCC. Silencing FAP inhibited the growth and metastasis of OSCC cells

in vitro and in vivo. Mechanistically, knockdown of FAP inactivated PTEN/PI3K/AKT and

Ras-ERK and its downstream signaling regulating proliferation, migration, and invasion in OSCC

cells, as the inhibitory effects of FAP on the proliferation and metastasis could be rescued by

PTEN silencing. Our study suggests that FAP acts as an oncogene and may be a potential

therapeutic target for patients with OSCC.

The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by

inactivating Lck. [链接]

通讯作者：谭泽华（台湾国家卫生研究院）Nat Commun. 2014 Apr 9;5:3618. doi:

10.1038/ncomms4618.

JNK pathway-associated phosphatase (JKAP, also known as DUSP22 or JSP-1) is a JNK activator.

The in vivo role of JKAP in immune regulation remains unclear. Here we report that JKAP

directly inactivates Lck by dephosphorylating tyrosine-394 residue during T-cell receptor (TCR)

signalling. JKAP-knockout T cells display enhanced cell proliferation and cytokine production.

JKAP-knockout mice show enhanced T-cell-mediated immune responses and are more susceptible

to experimental autoimmune encephalomyelitis (EAE). In addition, the recipient mice that are

adoptively transferred with JKAP-knockout T cells show exacerbated EAE symptoms. Aged

JKAP-knockout mice spontaneously develop inflammation and autoimmunity. Thus, our results

indicate that JKAP is an important phosphatase that inactivates Lck in the TCR signalling turn-off

stage, leading to suppression of T-cell-mediated immunity and autoimmunity.

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in

cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. [链接]

通讯作者：李培峰（中国科学院动物研究所）Nat Commun. 2014 Apr 7;5:3596. doi:

10.1038/ncomms4596

40

Abnormal mitochondrial fission participates in the pathogenesis of many diseases. Long

non-coding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs

operate in the regulation of mitochondrial network is unclear. Here we report that a lncRNA,

named cardiac apoptosis-related lncRNA (CARL), can suppress mitochondrial fission and

apoptosis by targeting miR-539 and PHB2. The results show that PHB2 is able to inhibit

mitochondrial fission and apoptosis. miR-539 is responsible for the dysfunction of PHB2 and

regulates mitochondrial fission and apoptosis by targeting PHB2. Further, we show that CARL can

act as an endogenous miR-539 sponge that regulates PHB2 expression, mitochondrial fission and

apoptosis. Our present study reveals a model of mitochondrial fission regulation that is composed

of CARL, miR-539 and PHB2. Modulation of their levels may provide a new approach for

tackling apoptosis and myocardial infarction.

Long-term exposure to decabrominated diphenyl ether impairs CD8 T-cell function in adult

mice[链接]

通讯作者：王艳（上海交通大学）Cell Mol Immunol. 2014 Apr 7. doi: 10.1038/cmi.2014.16.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate

to high levels in human populations that are subject to occupational or regional industry exposure.

PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their

effect on the immune system is not well understood. In this study, experimental adult mice were

intragastrically administered 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at doses

of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous

exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels

found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes,

decreased cytokine (IFN-γ , IL-2 and TNF-α ) production and lower CD8 T-cell proliferation

were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209

exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant

Listeria monocytogenes expressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had

reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure

causes adverse effects on the number and functionality of immune cells in adult mice.

An exceptionally preserved arthropod cardiovascular system from the early Cambrian. [链

接]

通讯作者：侯先光（云南大学）Nat Commun. 2014 Apr 7;5:3560. doi: 10.1038/ncomms4560.

The assumption that amongst internal organs of early arthropods only the digestive system

withstands fossilization is challenged by the identification of brain and ganglia in early Cambrian

fuxianhuiids and megacheirans from southwest China. Here we document in the

520-million-year-old Chengjiang arthropod Fuxianhuia protensa an exceptionally preserved

bilaterally symmetrical organ system corresponding to the vascular system of extant arthropods.

Preserved primarily as carbon, this system includes a broad dorsal vessel extending through the

thorax to the brain where anastomosing branches overlap brain segments and supply the eyes and

antennae. The dorsal vessel provides segmentally paired branches to lateral vessels, an arthropod

41

ground pattern character, and extends into the anterior part of the abdomen. The addition of its

vascular system to documented digestive and nervous systems resolves the internal organization of

F. protensa as the most completely understood of any Cambrian arthropod, emphasizing

complexity that had evolved by the early Cambrian.

Sulindac-Derived RXRα Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site.

[链接]

通讯作者：张晓坤&苏迎（厦门大学） Chem Biol. 2014 May 22;21(5):596-607. doi:

10.1016/j.chembiol.2014.02.017.

Retinoid X receptor-alpha (RXRα ), an intriguing and unique drug target, can serve as an

intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory

drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac

analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXR

α -dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα

(tRXRα ) with the p85α subunit of PI3K, leading to suppression of AKT activation and

induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with

K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different

from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXR

α modulators and define a binding mechanism for regulating the nongenomic action of tRXRα .

Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption

upon phosphorylation by RIP3. [链接]

通讯作者：王晓东（北京生命科学研究所 ) Mol Cell. 2014 Apr 10;54(1):133-46. doi:

10.1016/j.molcel.2014.03.003.

Programmed necrotic cell death induced by the tumor necrosis factor alpha (TNF-α ) family of

cytokines is dependent on a kinase cascade consisting of receptor-interacting kinases RIP1 and

RIP3. How these kinase activities cause cells to die by necrosis is not known. The mixed lineage

kinase domain-like protein MLKL is a functional RIP3 substrate that binds to RIP3 through its

kinase-like domain but lacks kinase activity of its own. RIP3 phosphorylates MLKL at the T357

and S358 sites. Reported here is the development of a monoclonal antibody that specifically

recognizes phosphorylated MLKL in cells dying of this pathway and in human liver biopsy

samples from patients suffering from drug-induced liver injury. The phosphorylated MLKL forms

an oligomer that binds to phosphatidylinositol lipids and cardiolipin. This property allows MLKL

to move from the cytosol to the plasma and intracellular membranes, where it directly disrupts

membrane integrity, resulting in necrotic death.

Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin

resistance in mice[链接]

通 讯 作 者 ： 甘 立 霞 ( 第 三 军 医 大 学 )Cell Rep. 2014 Apr 10;7(1):223-35. doi:

42

10.1016/j.celrep.2014.02.047

Overnutrition activates a proinflammatory program in macrophages to induce insulin resistance

(IR), but its molecular mechanisms remain incompletely understood. Here, we show that saturated

fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR,

suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice

aggravates HFD-induced glucose intolerance and IR, which is associated with augmented

systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages.

CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome

proliferator-activated receptor (PPAR)γ signaling. Consequently, they overproduce reactive

oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3

inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages

from oversecreting proinflammatory cytokines and from inducing proinflammatory signaling and

IR in the cocultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and

IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of

overnutrition-induced NLRP3 inflammasome activation in macrophages.

Evolution of Alu Elements toward Enhancers[链接]

通讯作者：韩敬东(中国科学院上海生命科学研究院)Cell Rep. 2014 Apr 24;7(2):376-85. doi:

10.1016/j.celrep.2014.03.011.

The human genome contains approximately one million Alu repetitive elements comprising 10%

of the genome, yet their functions are not well understood. Here, we show that Alu elements

resemble enhancers. Alu elements are bound by two well-phased nucleosomes that contain

histones bearing marks of active chromatin, and they show tissue-specific enrichment for the

enhancer mark H3K4me1. A proportion of Alu elements were experimentally validated as bona

fide active enhancers with an in vitro reporter assay. In addition, Hi-C data indicate that Alus show

long-range interactions with gene promoters. We also find that Alus are generally more conserved

when located in the proximal upstream region of genes. Their similarity to enhancers becomes

more prominent with their age in the human genome, following a clear evolutionary continuum

reminiscent of the evolutionary pattern of proto-genes. Therefore, we conclude that some Alu

elements can function as enhancers and propose that many more may be proto-enhancers that

serve as a repertoire for the de novo birth of enhancers.

Lysine glutarylation is a protein posttranslational modification regulated by SIRT5[链接]

通讯作者：赵英明(中国科学院上海药物研究所)Cell Metab. 2014 Apr 1;19(4):605-17. doi:

10.1016/j.cmet.2014.03.014.

We report the identification and characterization of a five-carbon protein posttranslational

modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by

immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and

biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5

43

(SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191

proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial

proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea

cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for

deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell

lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric

acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and

increases our understanding of the deacylase SIRT5

Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome[链接]

通讯作者：王卫庆&王俊&宁光(上海交通大学&华大基因、澳门科技大学、香港大学&上海

交通大学、中国科学院上海生命科学研究院）Science. 2014 May 23;344(6186):913-7. doi:

10.1126/science.1249480

Adrenal Cushing's syndrome is caused by excess production of glucocorticoid from adrenocortical

tumors and hyperplasias, which leads to metabolic disorders. We performed whole-exome

sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing

adrenocortical adenomas (ACAs), adrenocorticotropic hormone-independent macronodular

adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a

hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and

validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation,

which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA

substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently

mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight

potentially functional mutated genes in adrenal Cushing's syndrome.

Iron metabolism regulates p53 signaling through direct heme-p53 interaction and

modulation of p53 localization, stability, and function[链接]

通讯作者：胡荣贵（中国科学院上海生命科学研究院）Cell Rep. 2014 Apr 10;7(1):180-93. doi:

10.1016/j.celrep.2014.02.042

Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with

underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for

chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report

that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron

polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both

nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron

deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of

wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus

identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which

not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also

help predict and improve outcomes in iron-deprivation-based chemotherapy.