Tumor suppressor genes

2. TUMOR SUPPRESSOR GENES

3. TUMOR
SUPPRESSOR
GENES
 • genes which are involved in normal cell
regulation by negatively controlling progression
through the cell cycle
 • identified as genes that prevent the onset of
cancer and tumour growth.
 more specifically, they have all been found to be
involved in one or more of the following
functions: •inhibition of cell division
•DNA repair
•apoptosis
 • many TS genes with various functions have
been identified to date including: p53, pRB,
TGF–β, APC,NF1, NF2,BRCA1, BRCA2

5. RBGENE
Retinoblastoma gene
Location: long arm (q) of
chromosome 13
Codes for nuclear transcription
protein called pRB
Present in every human cell
Exist in both active and inactive
form

6. RBGENE

7. MUTATED
FORMOF RB
GENE
The mutant form of RB gene is involved in
several tumors mainly retinoblastoma.
It occurs in 2 forms:
Sporadic Retinoblastoma: Both the somatic
mutations in 2 allelles are acquired after
birth
Inherited/Familial Retinoblastoma: All
somatic cell acquire one mutant RB gene
from a carrier parent. Later during life the
other mutational event of second allelle
affecting the somatic cell occurs. This forms
the basis of two-hit hypothesis given by
Knudson in 1971

8. MUTATED
FORMOFRB
GENE

9. MUTATED
FORMOFRB
GENE

10. p53
GENE(TP53)
Protector of the genome
Location: short arm (p arm) of chromosome 17.
Normally present in small amounts
Accumulate only after DNA damage.
2 major functions of p53 in normal cell cycle:
i)in blocking mitotic activity: p53 inhibits
cyclins and CDKs and prevents the cell to enter
G1 phase transiently. This time is utilised by
the cell to repair DNA damage.
ii) in promoting apoptosis: p53 directs cells
which cannot be repaired by inbuilt system to
apoptosis by activating apoptosis inducing BAX
gene.

11. p53GENE

12. MUTATEDp53
GENE
In its mutated form, it ceases to act as
protector or growth suppressor but instead
acts as growth promoter or oncogene
Homozygous loss of p53 gene➡️genetically
damaged and unrepaired cells survive and
proliferate➡️malignant transformation
Eg: cancers of lung , head and neck, colon
and breast.
Mutated p53 is also seen in the sequential
development of cancer from hyperplasia to
carcinoma in situ and into invasive
carcinoma

13. MUTANTp53
GENE
Rarely, both alleles of p53 gene
becomes defective.( Knudson two
hit hypothesis)
This defect predisposes the
individual to develop cancers of
multiple organs ( breast,
bone, brain, sarcomas etc) ➡️ LI
FRAUMENI SYNDROME

14. MUTANTp53
GENE

15. TRANSFORMING
GROWTH
FACTOR-β(ΤGF-β)
 Inhibitor of cell proliferation
 Especially in epithelial, endothelial
and haematopoietic cells.
 Acts by binding to TGF-β receptor
forming a complex
 This complex acts in G1 phase of cell
cycle at 2 levels:
 1) Activates CDK inhibitors with
growth inhibitory effect
 2) Suppresses growth promoter genes
such as MYC, CDKs and cyclins

16. MutantTGF-β
Impairs growth inhibiting effect
and permits cell proliferation
Seen in cancers of pancreas, colon,
stomach and endometrium

17. APCGENEAND
β-CATENIN
PROTEIN
Adenomatous polyposis coli.
Normally inhibitory to mitosis
which takes place by a protein β-
catenin
β-catenin has 2 functions:
1) binds to cytoplasmic E-cadherin
that is involved in intercellular
interactions
2) activates cell proliferation
signalling pathway

18.  In colon cancer cells, APC gene is lost
and thus beta catenin fails to get
degraded allowing the cancer cells to
undergo mitosis
 Patients born with one mutant APC
gene allelle develop large number of
polyps in colon
 Later, loss of second APC gene allelle
occurs and malignant transformation
of one or more polyps develop.

19. OTHER
ONCOGENES
BRCA1 and BRCA2
Breast cancer susceptibility genes
BRCA1 located on chromosome 17
BRCA2- Chromosome13
Women with inherited defect in
BRCA1 have high risk of
developing breast and ovarian
cancer

20.  VHL Gene
 Located on chromosome 3p
 Mutation of this gene results in
activation of genes that promote
angiogenesis, survival and
proliferation.
 This causes von Hippel-Lindau
disease which is a rare autosomal
dominant disease characterised by
benign and malignant tumors of
multiple tissues
 VHL gene is found inactivated in 60%
cases of renal cell carcinoma

21. WILMS’ TUMOR GENE
WT1 and WT2 located on
chromosome 11
Prevent neoplastic proliferation of
cells in embryonic kidney
Mutant form of WT1 and WT2 seen
in hereditary Wilms’ tumor

22. NEUROFIBROMA (NF) GENE
They prevent proliferation of
Schwann cells
2 mutant forms: NF1 and NF2 –
seen in neurofibromatosis type 1
and type 2