ONCOGENE & Tumor suppressor gene .......

Cancer

1. JIWAJI UNIVERSITY
SCHOOL OF STUDIES IN BIOTECHNOLOGY
PRESENTED BY –
ASHISH SHARMA
(2
nd
SEMESTER )
SUPERVISED BY –
DR. RICHA BHARGAVA
ONCOGENE & TUMOR SUPPRESSOR GENE

2. Introduction
What is Cancer ?
•Cancer is characterized by uncontrol cell proliferation resulting from cumulative
genetics mutations and epigenetic modifications that disrupt normal regulatory
mechanism.
Key concepts :
ONCOGENE: Oncogene are mutated or overexpressed versions of normal
protooncogenes that drive cell division( proliferative advantage to cells ).
TUMOR SUPPRESSOR GENE : Genes that normally restrain cell division( halt cell
cycle progression ) , repair DNA damage or induce apoptosis.

3. Historical Background
Year Discovery Scientist(s) Significance
1911 Rous Sarcoma VirusPeytonRous First link between viruses and
cancer
1970s Proto-Oncogenes Bishop & VarmusNormal genes can cause cancer
if mutated
1971 Two-Hit HypothesisAlfred KnudsonExplain how tumor suppressor
genes works
1989 p53 Discovery Lane & Levine First identified tumor
suppressor gene
2000 Hallmarks of cancerHanahan &
Weinberg
Cancer arises through genetic
instability

4. Cell cycle checkpoints
CheckpointRegulating
Gene
Function Outcome if
mutated
G1/S p53 , RB DNA damage
check
Cancer
initiation
G2/M ATM , BRCA1DNA repair prior
to Mitosis
Genomic
instability
Mitotic APC Spindle assembly
check
Aneuploidy
Significance: Quality control ; failure leads to genomic
instability & tumorigenesis.

5. Oncogene
Activation Type Example Cancer Type
Point MutationRas Colon cancer
Gene AmplificationHER2 , Myc Breast cancer
Chromosomal
Translocation
BCR-ABL Chronic Myeloid
Leukemia
Viral IntegrationHPV E6 & E7 Cervical cancer
Oncogene Activation Mechanism :
Origin of name : The term
“ONCOGENE” was first coined by
Robert Weinberg in the 1980s.
Definition : Oncogene are mutated
or overexpressed version of normal
Proto-oncogene that drive cell
divisions .

6. Ras Signaling Pathways
Ras Proteins (GTPases) relay signals from
membrane receptors to the nucleus.
Pathway Steps:
Growth Factor Binding
(Activates receptor tyrosine kinase)
Ras Activation
(GTP binding induces an Active state)
Raf Activation
(Initiates the MAPK cascades)
MEK & REK
(Sequential phosphorylation events lead to
gene transcription & cell division)

7. Tumor Suppressor Gene
Origin of name : The term
“Tumor Suppressor Gene” was
first proposed by Alfred
Knudson in the 1971.
Definition : Gens that normally
restrain cell division , Repair
DNA damage or induces
apoptosis.
Tumor Suppressor
Gene
Function Associated Cancer
p53 (Guardian of
the genome)
DNA damage
response
50% of all Cancers
RB
(Retinoblastoma)
G1/S Checkpoint Retinoblastoma ,
Osteosarcoma
BRCA1/BRCA2 DNA Repair Breast , Ovarian
Cancer
PTEN Cell Proliferation
Inhibition
Prostate , Brain
Cancer
Major Tumor Suppressor Genes :

8. p53 Tumor Suppressor Pathways
Actsasatranscriptionfactorthatrespondsto
cellularstressandDNAdamage.
p53 Mechanism:
DNA damage detection
(Sensors [ATM/ATR] activate p53)
p53 Activation
(Accumulates and induces Expression of p21[cell
cycle arrest], Baxand PUMA [pro-Apoptotic
factor])
Cell fate decision
(Prevents propagation of damaged DNA , i.e.,
cells either arrest the cell cycle to repair damage
or undergo Apoptosis if the damage is
irreparable by inhibiting Bcl-2pathway)

9. Proto-Oncogene
Promote cell growth , cell survival or proliferation .
Gain-of-Function mutation ; converts it into
oncogene leading to excessive cell proliferation .
Dominant mutation ( mutation in one allele is
enough for oncogenic effect ) .
Ras , Myc , EGFR , HER2 , etc.
Tumor Suppressor Gene
Inhibits cell proliferation , promotes DNA repair and
induce Apoptosis .
Loss-of-Function mutation ; leads to unregulated
cell proliferation and cell survival .
Recessive mutation ( both allele must be mutated
for effect ) .
p53 , RB , PTEN , BRCA1 , BRCA2 , etc.
Normal Function
Example of Genes
Mutation Types
Effects of Mutation

11. Cancer Development Pathway
Step-By-Step Process :
Genetic Mutation
( Proto-Oncogene activation or Tumor
Suppressor loss )
Clonal Expansion
( Accumulation of mutations and selective
growth advantage )
Angiogenesis
( Tumor stimulates new blood vessel formation )
Invasion & Metastasis
( Tumor cell invade surrounding tissues and
Disseminate )

12. Conclusion
The balance b/w Oncogene activation and Tumor Suppressor gene inactivation lies at the core of
Cancer biology .
Future outlook : Integration of A.I. , CRISPR , and personalized medicine will usher in a new era of
cancer therapeutics .
# Curiosity note : -Telomeraserepresents a Novel Proto-Oncogene ( full length telomeres are
approximately 15 kb long ). In germ lines cells telomerase , a reverse transcriptase , adds a Hexameric
DNA repeat to the end to maintain full telomere length after DNA replication . As cell differentiate
during fetal development , telomerase function declines & the telomeres shorten with each
successive round of DNA replication , the telomere shorten by about 35 bases .Ultimately , as
telomeres shorten chromosomes end become damaged and cells stop dividing ; may be the cause of
normal cellular senescence . In transformed cells and many tumors , telomerase activity reappears
enhancing the ability of tumor cells to divide without limit . Telomerase activity has been detected in
more than 30 cancers types , and in over 80% cancers samples .

13. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5),
646–674.
Knudson, A. G. (1971). Mutation and Cancer: Statistical Study of Retinoblastoma. Proceedings of
the National Academy of Sciences.
Vogelstein, B., & Kinzler, K. W. (2004). Cancer Genes and the Pathways They Control. Nature
Medicine.
Images source : Internet .
Lane, D. P., & Levine, A. J. (1992). p53 Research: The Past, Present, and Future. Nature Reviews
Cancer.
Oncogene & Tumor Suppressor gene . Lecture notes of OSMOSIS.org .
Downward, J. (2003). Targeting RAS Signaling Pathways in Cancer Therapy. Nature Reviews
Cancer.
References

14. “ May our Quest for Knowledge and our pursuit
of innovative Solutions Create a Future where
Cancer is no longer a death sentence . ”
-Catimere

15. THANK YOU