2. Proto-oncogenes and Oncogenes
Proto-oncogenes encode proteins that are involved in the control of cell growth.
Alteration of the structure and expression of proto-oncogenes can activate them to
become oncogenes capable of inducing tumor.
Oncogenes are cancer causing genes, Originally isolated from virus that infect cell and
cancer.
Oncogenes can be classified into FIVE groups based on the functional and biochemical
properties of protein. These groups are
1.Growth Factors
2.Growth Factor Receptors
3.Signal Transducers
4.Transcription Factors
5.Programmed Cell Death Regulators
4. Three types of Mutation Converts Proto-oncogenes into
oncogenes
5.
6. HER2/neu and Breast Cancer
The HER2 gene encodes a receptor tyrosine kinase closely related to the
epidermal growth factor(EGF) receptor.
Mechanism by which HER2 is overexpressed is gene amplification, which
results in multiple copies of the gene accumulating in tumor cells.
The increased level of HER2 tyrosine kinase receptor on tumor cells results in
increased signaling via Ras-MAPK pathway leads to cellular proliferation.
7. Activation of Ras
The human genome encodes three Ras genes: H-ras, K-ras, N-ras.
70-90% of pancreatic carcinomas contain a mutation in the K-ras gene.
Ras oncogenes are activated by point mutations that result in proteins unable
to hydrolyze GTP.
Ras proteins are therefore locked in the GTP bound form, which continually
activates MAPK pathway, which leads to cell proliferation.
8. Chromosomal rearrangements – altered regulation
Burkitts lymphoma
All patients show t(8:14)
translocation of the immunoglobulin gene
on chromosome 14 to the c-myc
oncogene locus on chromosome 8
c-myc is under regulatory control of IgH
resulting in overexpression of the
oncogene
9. Chromosomal rearrangements - fusion gene
Chronic Myelogenous Leukaemia Translocation t(9:22)
Abl-bcr fusion gene encodes a constitutively active protein tyrosine kinase, which affects
cell cycle, adhesion and apoptosis
10. Myc Oncogene
The Myc protein acts in the nucleus as a signal for cell proliferation through
several mechanisms.
Myc is made active by chromasomal translocation.
11. Tumor Suppressor Genes
Tumor Suppressor gene Can be defined as genes which encode proteins
normally inhibit the formation of tumors.
Mutations in tumor suppressor genes contribute to the development of cancer
by inactivating that inactivating function.
Mutation of this type are termed Loss-of-Function mutations.
Inactivation of both copies of tumor suppressor gene is required before their
function can be eliminated.
Mutations in Tumor Suppressor genes are recessive at the level of an
individual cell.
Tumor Suppressor genes divided into two general groups: Promoters and Care
Takers.
Promoters are tumor suppressor like p53 and RB.
Caretaker genes are responsible for processes that ensure the integrity of the
genome, such as those involved in DNA repair.
19. BRCA1 and BRCA2
BRCA1 located on 17q21 and BRCA2 13q12 are tumor
suppressor genes associated with breast and ovarian
cancer.
The genee products encodedd by BRCA1 and BRCA2 are
nuclear proteins that co-localize with RAD-51 at the sites
of DNA damage, and play a role in homologous
recombination repair of double stranded breaks.
BRCA1 and BRCA2 leads to frameshifts resulting in
missing or non-fuunctional protein.
