This document discusses oncogenes and tumor suppressor genes, which are critical cancer genes. It defines oncogenes as mutant, overactive, or overexpressed versions of normal proto-oncogenes, which promote cell growth. Tumor suppressor genes normally inhibit growth or promote cell death. Activation of oncogenes or inactivation of tumor suppressor genes can cause cancer. Examples of important oncogenes discussed include SRC, RAS, and MYC. Key tumor suppressor genes mentioned are P53, RB, and BRCA1/2. The document outlines several mechanisms by which these genes can become mutated and dysfunctional, ultimately leading to uncontrolled cell growth and cancer.

1. Department of clinical biochemistry
university of Kashmir
Topic : Oncogenes And Tumor Suppressor Genes
ADIL WANI

2.  The cancer may be defined as autonomous proliferation of cells which are
unresponsive to growth factors or growth signals.
 Cancer Critical Genes :Two Categories
 Proto-oncogenes – normal constituents of cells whose function is to promote
proliferation or cell survival.
These genes can code for growth factors, growth factor receptors, signal
transduction proteins, intracellular kinases and transcription factors.
 Oncogenes – These are the mutant , over active or overexpressed forms
of the proto-oncogene.
 Tumor suppressor genes (normal growth suppressor genes)
-- encode proteins that inhibit proliferation, promote cell death, or
repair DNA
Activation (mutation) of oncogenes or absence /inactivation
of tumor suppressor genes can lead to cancer.

3. SRC is first discovered oncogene (Vogt & Martin)
Discovered in Rous sarcoma virus , carrying an oncogene (src) that
causes cancer in chickens (SRC protein tyr kinase).
First human oncogene discovered was ras (Mutant version of normal
proto-oncogene)
5 mechanisms of activation for oncogenes:-
1.Promoter insertion
2.Enhancer insertion
3.Chromosomal translocation e.g. myelogenous leukemia
4.Gene amplification .
5.Point mutations e.g. ras

6. 1. Promoter Insertion eg. avian leukemia
viruses
2. Enhancer Insertion
The myc protein acts as a transcription factor and it controls the
expression of several genes.
Mutations in the myc gene have been found in many different
cancers, including Burkitt's lymphoma, B-cell leukemia, and lung
cancer.

7. 3. Chromosomal translocation
Chronic myeloid leukemia
The bcr/abl fusion, created on the
chromosome 22, encodes a chimeric
protein of 210 kDa, with increased/
unregulated tyrosine kinase activity ,
involved in cell transformation.
: Burkett's lymphoma

8. 4. Mutations
• In human tumors the most characterized oncogene
mutations are base substitutions (point mutations) that
change a single amino acid within the protein.
• Mutations activate proto-oncogenes through structural
alterations. These alterations, which usually involve critical
protein regulatory regions, often lead to the uncontrolled,
continuous activity of the mutated protein.

9. • Point mutations (Gly- val) are frequently detected in
the ras family of proto-oncogenes (K-ras, H-ras, and N-ras).
• Single most dominant cause of many human tumor.

10. Transcription of
cyclin D1 gene
Ras protein imp.
Role in mitogenic
signaling

11. A Large Group Of Oncogenes Encode Growth Factor
Receptors mostly Protein Tyr Kinases e.g. PDGF
Tel
Tel /PGDRF
Oncogene protein
Kinase
activity
Kinase
constitutively active

12. Tumor suppressor genes are normal genes that slow down cell
division , repair mistakes or tell cell to die.
Mutation in TSGs are recessive at the level of individual
cell.
 First insight intoTSG came from somatic cell hybridization
experiments
Normal Harris et al., 1969
Tumor suppressor genes

13. Studies of Rare Hereditary Cancer
Syndromes First Identified Tumor
Suppressor Genes
 Retinoblastoma is a cancerous tumor of the retina. It occurs in
two forms:
 Familial retinoblastoma (hereditary)
 Sporadic retinoblastoma (nonhereditary)
 Some tumor suppressor genes
 P53 , Rb , BRCA1 and 2 , APC and DCC , PTEN
and PPA2 , LKB1 , P16 , WT1 and WTX
 Mechanism of tumor suppression gene inactivation
 Deletion,DNA methylation, binding viral oncoproteins ,
loss of heterogeneity.
Retinoblastoma

14. Knudson’s hypothesis

15. The Rb protein prevents cells from entering S
phase of the cell cycle
c-myc and
c-fos.

16.  P53
 Gene encodes a phosphoprotein with 53 kDa with 375 a.a
 It is a transcription factor regulating the cell cycle and apoptosis.
 It block the cells that have damaged DNA by triggering the production
of another protein P21, which blocks cell division until the damage is
repaired.
 If DNA damage is serve, P53 directs the cell to commit suicide by
apoptosis program
 Most tumors have a complete absence of P53 ,other show mutation that
lead to non function P53
 Inheritance of a mutation in p53 leads to Li-Fraumeni syndrome.

17. GADD
(Growth
Arrest DNA
Damage)
Activates two
apoptotic
gene bax and
IGFBP3

18. NF-1 regulates ras by activating
GTPase activity
oncogenes: myc and ras
tumour suppressor p53 gene

19. Human Papillomavirus (HPV
 The name anti-oncogene.
 Both Rb & P53 forms complex with some
HPVs
 HPV Synthesizes E7 &E6 Proteins.
 E7 now binds Rb protein preventing it from
biding E2F,hece myc remains free.
 E6 bind P53 and targets it for proteodomal
degredation.

20. END