LEHNINGER PRINCIPLES OF BIOCHEMISTRY

Fifth Edition

David L. Nelson and Michael M. Cox

© 2008 W. H. Freeman and Company

CHAPTER 28 Regulation of Gene Expression 발현조절 원리, 원핵, 진핵에서 발현 조절

Seven processes that affect the steady-state concentration of a protein

E. coli promoters

Consensus sequence for many E. coli promoters

유전자 발현의 조절 * repressor : promoter에 RNA polymerase 결합방해 (원핵)

* silencer : 전사억제 ⇒ negative regulation (진핵)

* operator : DNA상 repressor가 결합하는 자리 (원핵)

* activator : RNA polymerase-promoter 상호작용 강화

⇒ positive regulation

* enhancer : 활성인자가 결합

* operon : 1개의 promoter가 제어에 관여하는 복수의 유전자구조

activator repressor

DNA enhancer promoter operator (원핵) A B C

(진핵) silencer (진핵)

조절서열 단위로서 전사된 유전자

*House keeping gene: constitutive gene expression

*Regulated gene expression: inducible, repressible

*polycistronic cf)monocistronic

Common patterns of regulation of transcription initiation

Representative bacterial operon

Lactose metabolism in E. coli.

1. Lac operon 1) Lactose가 없는 경우→lactose operon 전사는 일어나지 않음

2) Lactose가 있는 경우→전사진행

3. Transcription factors의 구조 motif 1) helix-turn-helix

2) zinc finger

3) leucine zipper

4) helix-loop-helix

5) homeodomain : homeobox

4. Chromatin remodeling

5. Transactivator and coactivator

6. Hormone response elements (HREs)

Helix-turn-helix

Helix-turn-helix

DNA 결합영역

Ex) Pit, Oct, Unc

Zinc fingers

Sp1, Steroid receptor

Leucine zippers

Myc, Fos, Jun

Helix-loop-helix

Max(tf) E12, MyoD

•Glucose효과

1) lactose(+)/glucose(+):

glu때문에 cAMP↓ → cap도 promoter에 결합하지 않음

→ lac mRNA↓

2) lactose(+)/glucose(-):

glu(-) → cAMP↑ → cAMP-cap복합체 형성 → promoter에

결합 → repressor도 lactose에 의해 억제/cAMP-cap가

RNA polymerase 결합촉진 →lac mRNA↑

* cap (catabolite gene activator protein) = cAMP receptor

protein (CRP)

CRP homodimer

cAMP

Combined effects of glucose and lactose on expression of the lac operon

진핵세포의 유전자발현 특성 1)전사활성은 chromatin구조와 관련 2)주로 + regulation 3)multimeric regulatory proteins 4)핵에서 전사는 번역과 시간,공간상 분리 * heterochromatin:condensed, inactive * euchromatin:less condensed, acive * hypersensitive site:활발한 전사(DNase에 감수성)

Chromatin remodeling :전사와 관련된 구조적 변화 *active chromatin: histone acetylation, Ubiquitination, less methylation(CpG site) By histone acetyltransferase(HAT)- active histone deacetylase(HDAC)-inactive

Promoter Regions of Several Representative Eukaryotic Genes

Response Elements are Promoter Modules Responsive to Common Regulation

Response Elements are Promoter Modules Responsive to Common Regulation

Figure 29.27 The metallothionein gene possesses several constitutive elements in its promoter (the TATA and GC boxes) as well as specific response elements such as MREs and a GRE. The BLEs are elements involved in basal level expression (constitutive expression). TRE is a tumor response element activated in the presence of tumor-promoting phorbol esters such as TPA (tetradecanoyl phorbol acetate).

효모에서

Basal tf

coactivator

High mobility group: ch remodeling and transpt에 중요

Eukaryotic promoters and regulatory proteins

Eukaryotic promoters and regulatory proteins

The components of transcriptional activation

Regulation of transcription of GAL genes in yeast

Gal 대사효소

Hormone Response Elements (HREs) Bound by Steroid-Type Hormone Receptors

* Cellular signal transduction

<세포의 자극에 의한 유전자 발현 조절>

Tf 인산화

* 호르몬과 표적기관 calcitonin : C세포에서 분비 Ca저하

GHIH PRIH

GHRH(GH) GnRH(CH,FSH) TRH(TSH) CRH(ACTH)

T3/T4

β α δ

뼈에서 유리 신장 재흡수 glucocorticoid

aldosterone

Translational regulation of eukaryotic mRNA

번역 조절

Gene silencing by RNA interference

Small temporal RNA

(RNAi)

Small interfering RNA

생명현상의 Overview : 생명현상의 분자기전 Information

생체정보 : hormone, cytokines, neurotransmitter→세포→유전

O2/영양분 cytokines neurotransmitters Hormones 1st messenger

당질 (당뇨병)

지질→저장 (비만, 동맥경화)

-omics

°Physiome

⋅Genome=gene+chromosome -sequencing -SNP DNA chip ⋅Transcriptome ⋅Proteome -2D/Mass

Hormesis

Maintenance

E小

Cell proliferation (replication)

E多

2nd messenger

⋅Southern blot ⋅ Northern blot

⋅ Western blot

단백질

열

Protein (생리기능)

Cell homeostasis

themogenin ATP

Vt C, E

a.a

mRNA Vt B AAA

TCA

NADH

Signaling

Transcriptome Epigenome

Proteome

Metabolome Lipidome

Gerontome

The major endocrine systems and their target tissues

ng

ug

mg

CRH

Overview of metaboilsm

Glycogenesis Glycogenolysis

F-1,6-bisphosphatase

F-6-P

Phosphofructokinase

Phosphoenolpyruvate kinase((PEPCK) FOXO1,HNF-4

단백질합성

Pyr dehydrogenase

Chol synthesis

HMG-CoA reductase Cholesterol

PPAR α/β

PGC1 α

PKA

cAMP

GProtein

Glucagon Epinephrine

Akt GSK3β

GS

Glycogen 합성

PI3K

IRS

Insulin S70S6K

mTOR

Glut4

Glu

Glu

IR

SREBP-1,2

PKA

CREB

PGC-1α

IRS

PI3K

FA합성 Chol합성 Glycogen합성

GSK3β

mTOR

S70S6K

S6protein

FOXO1, HNF-4 PPARα, β(δ)

gluconeogenesis β -oxidation

Fasting Diet

Akt

SREBP-1,2

Glucagon

cAMP

Insulin

CBP/p300

AMPK(AMP senser) Sirt1(NAD senser)