lecture 8 oncogene and anti-oncogene zhihong li (李志红)
TRANSCRIPT
Lecture 8
Oncogene and
anti-oncogene
Zhihong Li(李志红)
•Cells normally grow, reproduce and die in response to signals inside and outside the body in an orderly way.
•Malignant tissues can invade and damage other tissues and organs. Cancer cells can then break away from the tumour and enter the bloodstream or lymphatic system, spreading the cancer to other parts of the body. (metastasis)Benign Malignant
cancer
Normal cells
Cancer cells vs. normal cells: what's different?
Cancer Cell Do Not Grow Faster ThanCancer Cell Do Not Grow Faster Than
Normal CellsNormal Cells
Rather, Their Growth is Just Rather, Their Growth is Just
UncontrolledUncontrolled
Proliferation Differentiation Death
Cancer: disruption of cellular equilibrium
Proliferation Differentiation Death
Causes of Cancer
Heredity
Cancer - multi-step and multi-gene diseaseAll types of cancers are caused by changes in
genes.
Cancer - a genetic disease of somatic cells.
Cancer - the most common human genetic disease. Not every gene is involved in
carcinogenesis!Predominant mechanisms for cancers are: impairment of a DNA repair pathway transformation of normal genes into oncogenes malfunction of anti-oncogenes (tumor suppressor genes)
Relationship of oncogene, anti-oncogene and growth factor
Cellular control depends on a constant balance
Imbalance: proto-oncogenes over-expressed,
anti-oncogenes inactivated or lost.
proto-oncogenes - favour cell reproduction,
anti-oncogenes - prevent cell reproduction.
§1 Oncogene
oncogene: These genes code for proteins that are capabl
e of stimulating cell growth and division. In normal tissues and organisms, such growt
h-stimulating proteins are regulated, so that growth is appropriately limited.
However, changes/mutation in these genes may result in loss of growth regulation, leading to uncontrolled cell proliferation and tumor development.
Dominant mutation: one copy is sufficient to cause cancer. (different than tumor-suppressors, recessive mutation)
Oncogene
• found in viruses or as part of the normal genome. – v-onc: virus oncogene – c-onc: cellular-oncogene or proto-oncoge
ne
Virus- oncogene (v-onc)
• Genes are in viruses that can cause tumors in vivo and transform the cell in vitro.
• First link between viruses and cancer proposed by Francis Peyton Rous in 1910: – cell-free extracts from chicken
tumors injected into healthy chickens caused new tumors.
•In 1910, Peyton Rous found the first retrovirus (Rous Sarcoma Virus, RSV) in a chickens filtrated sarcoma.
•Rous got the Nobel Prize in Physiology and Medicine in 1966.
•Structure of RSV genome
9392 bp
LTR LTRgag pol env src
tyrosine kinase
526 residue
60 kD
wide type viral genes oncogene
to initiate
and regulate
transcription
Cellular Oncogene (c-onc)• Or proto-oncogene
– code for proteins that help to regulate cell growth and differentiation.
• Genes are in static or low-level expression state in normal cells under the normal situation.
• The proto-oncogene can become an oncogene due to mutations or increased expression.
Product and Function of Proto-oncogene
• Extracellular growth factors • Transmembrane growth factor recep
tors • Intracellular signal transduction prot
eins • Intranuclear transcription factors
Category and major product of c-oncogene
1. src family — tyrosine protein kinase2. ras familiy — P21 ( GTPase activity )3. myc familiy — intranuclear DNA bindin
g protein4. sis familiy — P28 (similar platelet deriv
ed growth factor)5. myb familiy — intranuclear transcripti
on factor
Mechanisms of Oncogene Activation
1. Obtaining a strong promoter or enhancer
2. Group translocation or chromosome rearrangements
3. Proto-oncogene amplification
4. Gene mutation
avian leukemiavirus genome
host cellgenome
ssRNA
dsDNA
c-mycLTR
to increase c-myc gene expression, 30-100 times, compare with no infection.
1) Obtaining a strong promoter or enhancer
c-Myc
• Myc (c-Myc) codes for a protein that binds to the DNA of other genes and is therefore a transcription factor.
• Myc protein regulate expression of 15% of all genes through binding on Enhancer Box sequences (E-boxes).
2) Gene translocation• Chronic myelogenous leukemia (CML) is a can
cer of the blood system in which too many white blood cells (WBCs) are made in the bone marrow.
• What causes CML?
– In almost everyone with CML, the genetic material (chromosomes) in the leukemia cells has an abnormal feature called the Philadelphia(Ph) chromosome.
•produces a new, abnormal gene called bcr-abl. This abnormal gene produces Bcr-Abl tyrosine kinase, an abnormal protein that causes the excess WBCs typical of CML.
ras or c-myc
expression of ras or c-myc is increased obviously
amplification
3) Proto-oncogene amplification
4) Point mutation
• Mutated in 30% of all cancers.
• A “molecular switch” in the signal transduction pathway leading from growth factors to gene expression controlling cell proliferation:
– GF receptor Ras TF target genes growth.
• A single amino acid change in Ras protein can cause constant stimulation of the pathway, even in the absence of growth factors.
Ras Proto-oncogene
Ras Proto-Oncogene
In response to growth factor binding at receptor, the Ras gene product combines with GTP
to promote cell division
In cancer cells, the RAS gene product is locked into its GTP-binding shape and does not require a signal at
the receptor in order to stimulate cell division
H-ras
GGC
GTC
Gly
Val
DNA Protein
carcinoma
normal
Genetic Disease Associated with Ras
• The altered H-Ras protein is permanently activated within the cell.
• This overactive protein directs the cell to grow and divide in the absence of outside signals, leading to uncontrolled cell division and the formation of a tumor---Bladder cancer.
• Ras family: H-Ras, K-Ras, R-Ras and N-Ras • The presence of ras mutations is detected in sev
eral human tumors- 90% of pancreatic, 50% of colon and 30% of lung.
§2 Anti-oncogene
Tumor suppressor gene (anti-oncogene)
• A gene whose protein products inhibit cell division, thereby preventing uncontrolled cell growth.
Tumour suppressor genes
Act as a brake for cell division
“Guardian of the genome”
PROBLEM:
Mutation in tumour suppressor genes = brakes don’t work, or there is an accumulations of mutations (DNA repair enzymes)
• Coding the restrained protein relating to cell cycle control.
• When tumor suppressive gene is deleted and mutated, there is an induced occurrence of tumors.
• Rb gene and P53 gene.
Functions of tumour suppressor genes
Retinoblastoma (Rb gene)
• Diagnosis: “Cat’s eye” reflection in affected eye.
• Most common cancer of infants and children (1/20,000 U.S. live births).
• Survival > 90% with early diagnosis and treatment.
• Individuals at greater risk of developing other cancers.
Recessive mutation
•People prone to retiPeople prone to retinoblastoma have noblastoma have onone mutated copy of the mutated copy of the Rb gene (Rb-)e Rb gene (Rb-) and and one normal copy (Rbone normal copy (Rb++). ).
• Conversion of the Conversion of the RbRb++ copy to Rb copy to Rb- - by mby mutation leads to uncoutation leads to uncontrolled growth of retntrolled growth of ret
inal cells.inal cells.
Knudson’s “Two-Hit” Model for Retinoblastoma
Normal Normal 2 intact copies2 intact copies
Predisposed Predisposed 1 intact copy1 intact copy1 mutation1 mutation
Affected Affected Loss of both Loss of both copiescopies
Modified from Modified from Time, Time, Oct. 27, 1986Oct. 27, 1986
Mechanism of action of Rb gene
E2F = transcription factorRb = product of Retinoblastoma
gene, inhibits action of E2F until chemically modified
P53 gene
• P53 gene encodes the protein which molecular weight is 53kD.
• The “Last Gatekeeper” gene since malignant state not attained despite the presence of other cancer-causing mutations until p53 is inactivated by mutation.
Biologic function of P53 protein
• Suppressing cell cycle• Suppressing transformation fun
ction of some oncogenes • Monitoring cell DNA damage • Inducing the cell apoptosis
Function of Tumor Suppressor Gene p53
• p53 initiates repair of damaged DNA• if DNA cannot be repaired, it initiates apoptosis
•Cancer is a multistep process
Oncogene activation
Oncogenic viruses
Environmental factors (physical and chemical)
Mutations
Inactive antioncogenes Carcinogenesis
Diminished regulation by apoptosis genes
A simplified hypothesis for the development of cancer
Points• Oncogene
– v-onc– c-onc (proto-oncogene)– Product and Function of Proto-oncogene
• Mechanisms of Oncogene Activation– Obtaining a stronge promoter or enhancer– Group translocation or chromosome rearra
ngements – Proto-oncogene amplification– Gene mutation
• Tumor suppressor gene (anti-oncogene)– Rb gene and P53 gene