An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered.

1. ONCOGENES
- Vishakha Upadhyay

2. • Oncogenes produce proteins that have the capacity to stimulate growth and
proliferation.
• Oncogenes are derived from proto oncogenes which are genes that encode
proteins having function in normal cells
• They are dominant or “gain of function” mutations.
• They may lead to genetic instability, preventing a cell from becoming a victim
of apoptosis or promote metastasis
• Different oncogenes become activated in different types of tumors, which
reflects variations in the signaling pathways that operate in diverse cell types.
Oncogenes

3. • The activity of the normal protein is regulated by another tyrosine kinase that
phosphorylates src at T-527 (p-527 src is inactive).
• v-src has a deletion in 18 aa at the C-T that includes T-527.
• Therefore , v-src or appropriate cellular mutants (c-src) have constitutive
tyrosine kinase activity, therefore unregulated cell growth and proliferation.
• All oncogenes have been found in normal cell equivalent genes/proteins and
are termed “proto-oncogenes”.
• First discovered through the ability of Rous sarcoma virus (RSV) to cause
cancer in chickens.
• Mutant studies of RSV: the src gene causes cancer!
• Transfection of cells with src or other oncogenes. e.g., ras or jun leads to
neoplastic transformation.
• “There is a normal cell equivalent of this so-called “oncogene” and it codes for
a protein that has been associated with tyrosine kinase activity, that stimulated
growth and proliferation via protein phosphorylation in signal transduction
pathways”.
Discovery of oncogenes

4. • Growth factors – rare but an example is sis which codes for a mutant PDGF
(platelet derived growth factor)
• aberrantly auto stimulates proliferation of cells containing PDGF receptors.
• Sis is present in cancer causing Simian Sarcoma Virus
• Cultured cells transformed with this virus secretes large amount of PDGF into
medium, which causes cells to proliferate in uncontrolled fashion
• Growth factor receptors- Oncogenes encoding cell surface receptors that
transduce growth promoting signals have been associated with several types of
cancer.
e.g., erb b is a mutant form of epidermal growth factor receptor. This receptor
functions as a tyrosine protein kinase (CT of protein) located on the cytoplamic
side of the membrane with the ligand binding region (NT of protein) facing the
cell exterior.
In erb b the receptor protein is missing the N-terminal ligand binding domain on
the cell surface exterior and the C-terminal tyrosine protein kinase is in a
permanently turned on state.
Oncoproteins

5. A point mutation
changes a normal RTK
into one that dimerizes
and is constitutively
activated even in the
absence of ligand
A single point mutation
converts the normal
Her2 receptor into new
oncoprotein-
Neuroblastoma

6. • Intracellular transducers e.g., ras (a mutant form of an inner cell surface GTPase) ,
whose function activates a number of other regulatory factors including another
oncogene termed raf (a protein kinase) that work in concert to regulate cell
proliferation via the MAP Kinase Pathway which activates transcription factors
proto-oncogene = ras
Oncogene = mutated ras
Always activated
Always stimulating
proliferation

7. amino acid position
Ras gene 12 59 61 Tumor
c-ras (H, K, N) Gly Ala Gln normal cells
H-ras Gly Ala Leu lung carcinoma
Val Ala Gln bladder carcinoma
K-ras Cys Ala Gln lung carcinoma
Arg Ala Gln lung carcinoma
Val Ala Gln colon carcinoma
N-ras Gly Ala Lys neuroblastoma
Gly Ala Arg lung carcinoma
Murine sarcoma virus
H-ras Arg Thr Gln Harvey strain
K-ras Ser Thr Gln Kirsten strain
Amino acid substitutions in Ras family proteins (inactivates GTPase)

8. • Nuclear transcription factors like myc.
The myc protein is a key factor involved in activation of gene transcription
in cells going from a non –proliferating state. Stimulates transcription of
genes that promote progression through G1 phase of cell cycle and G1 to
S transition
If myc gene expression is blocked using anti-sense oligonucleotides, cell
cycle progression is stopped. Over expression of c-myc is characteristic of
many cancers.
Conversion of c Myc proto oncogene can occur via different mechanisms
such as translocation under constitutive active promoter
• Oncogenes that encode products that affect Apoptosis
Apoptosis is process of distruction of cancerous cells. Inability to carry on
apoptosis can result in tumor
e.g., Bcl2 proto oncogene

9. Activation mechanisms of proto-oncogenes
proto-oncogene --> oncogene

11. Hyperactivation of Myc

13. CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS
Neoplasm Translocation Proto-oncogene
Burkitt lymphoma t(8;14) 80% of cases c-myc1
t(8;22) 15% of cases
t(2;8) 5% of cases
Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2
leukemia
Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2
Leukemia
1c-myc is translocated to the IgG locus, which results in its activated expression
2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase

15. GENE AMPLIFICATION
Oncogene Amplification Source of tumor
c-myc ~20-fold leukemia and lung carcinoma
N-myc 5-1,000-fold neuroblastoma
retinoblastoma
L-myc 10-20-fold small-cell lung cancer
c-abl ~5-fold chronic myoloid leukemia
c-myb 5-10-fold acute myeloid leukemia
colon carcinoma
c-erbB ~30-fold epidermoid carcinoma
K-ras 4-20-fold colon carcinoma
30-60-fold adrenocortical carcinoma

18. Oncogenic retroviruses
• Cancer is a genetic disease- oncogenesis consists of the processes that
result in growth of cells in which mutations have accumulated
• Viruses are a contributing factor in about 20% of all human cancers
• Growth properties and morphologies of cultured cells could be changed
upon infection with certain viruses- cells become transformed
• Cells become immortal in an early step in oncogenesis-they continue to
grow and divide even though the body has sufficient numbers of these cells
• They lose contact inhibition and the need to adhere to a surface
• They look different, more rounded

19. • Oncogenesis is the result of genetic changes
that alter the expression or function of proteins
that play critical roles in the control of cell
growth and division
•Oncogenic viruses cause cancer by inducing
changes that affect cell growth and division
• Cancer arises from a combination of
dominant gain of function mutations in proto-
oncogenes and recessive loss of function
mutations in tumor suppressor genes
Oncogenic viruses

20. • Oncogenic viruses were discovered by Ellerman and Bang in 1908 who
showed that avian leukemia can be transmitted by filtered extracts of
leukemic cells
• In 1911 Peyton Rous showed that solid tumors can be produced in chicken
using cell free extracts

21. Oncogenic retroviruses are classified into two groups:
1) Transducing oncogenic retroviruses:
- highly carcinogenic, cause malignancies in 100% of the infected animals in a
matter of days
- cause cancer because their genomes contain transduced cellular genes that
become oncogenes
-virally transduced versions of cellular genes are called v-oncogenes, their
cellular counterparts are called c-oncogenes or proto-oncogenes
2) Nontransducing oncogenic retroviruses:
-less carcinogenic
-do not encode cell derived oncogenes
-activate transcription of proto-oncogenes by integration of the provirus close to
these genes in the host genome
-Additional mutations are required
- common

22. THANKYOU