Tumor suppressor genes regulate cell growth and division. When functioning properly, they inhibit tumor formation but when mutated or inactivated, they lose this ability. Examples include p53, Rb, APC, BRCA1, BRCA2. p53 is mutated in 50% of cancers and regulates DNA repair/cell cycle arrest or apoptosis. Li-Fraumeni syndrome results from germline p53 mutations increasing cancer risk. The APC gene regulates beta-catenin to control cell growth. Mutations in tumor suppressor genes are often required for tumor development according to the two-hit hypothesis as seen with retinoblastoma caused by Rb mutations.

1. ACHARIYA ARTS AND SCIENCE COLLEGE
(AFFILATED TO PONDICHERRY UNIVERSITY)
DEPARTMENTAL SEMINAR
BIOTECHNOLOGY DEPARTMENT
TOPIC:-TUMOUR SUPPRESSOR GENE
Presentation by
Gopi Krishna Giri

2. Tumor Suppressor Genes
Guided by
Dr.DE.Salamun

3. TUMOR
 A tumor, also known as a neoplasm, is an
abnormal mass of tissue which may be solid or
fluid-filled.
 A tumor does not mean cancer - tumors can
be benign (not cancerous), pre-malignant
(pre-cancerous), or malignant (cancerous).

4. CANCER
 The name for diseases in which the body's
cells become abnormal and divide without
control.
 They may spread through the bloodstream
and lymphatic system to other parts of the
body.

6. WHAT IS TUMOR SUPPRESSOR GENE ?
 Tumor suppressor genes are genes that regulate the
growth of cells. When these genes are functioning
properly, they can prevent and inhibit the growth of
tumors.
 When tumor suppressor genes are altered or
inactivated (due to a mutation), they lose the ability
to make a protein that controls cell growth.

7. Categories of tumor suppressor genes
 Caretaker genes:
Maintain the integrity of the genome by repairing
DNA damage
 Gatekeeper genes:
Inhibit the proliferation or promote the death of
cells with damaged DNA

8. Tumor suppressor genes: functional categories and tumor association
Category
Gene
Function
Tumor susceptibility if
germ line mutation
Comments
Gatekeepers
p53
Transcription
factor
Li-Fraumeni syndrome
Also mutated in 50% of
human cancers
Rb1
Transcriptional
regulator
Familial
retinoblastoma
Often mutated in other
cancers
APC
Regulates βcatenin function
Familial adenomatus
polyposis
Often mutated in
sporadic colorectal
cancers
BRCA1
DNA repair
Breast and ovarian
cancer
Rarely mutated in
sporadic breast cancers
BRCA2
DNA repair
Breast cancer(female
and male)
MSH2
MLH1
DNA mismatch
repair
Hereditary nonpolyposis colorectal
cancer
Caretakers
Mutation permits
further mutations

9. Retinoblastoma(Rb) gene
 First phenotypic cancer suppressor gene to be
discovered
 Responsible for retinoblastoma, a malignant
tumor of retina, a rare childhood tumor
 60% are sporadic (non-inherited), remaining
ones are familial

10. Two-hit hypothesis
 To account for the sporadic and familial
occurrence of retinoblastoma, Knudson, in 1974
– Two mutations(hits) are required with Rb gene ,
located 13q14, for the development of
retinoblastoma
– In familial cases, children inherit a defective copy of
Rb gene, the other copy is normal. Retinoblastoma
develops when the normal copy undergo somatic
mutation
Recessive disorder, Transmitted as dominant trait
– In sporadic cases, both normal Rb alleles are lost by
somatic mutation in one of the retinoblasts.

11. The “two-hit" origin of retinoblastoma

12. p53 Gene
 Situated at the short arm of the chromosome
1
 It is also called TP53 or tumor protein codes
for protein that regulate the cell cycle
 Normal functions p53
Repair of damaged DNA before S-phase in the
cycle by arresting the cell cycle in G1 until the
damage is repaired
Apoptosis cell death if there is extensive DNA
damage

13. p53 Gene
 P53 level raise in cells with sustained cell
damage, until the damage is repaired or cell
undergoes apoptosis.
 Prevents propagation of possibly mutated
cells.
 Called “the guardian of the genome”.

14. P53 gene
 Involved directly in DNA repair
 Transcriptional target gene p53R2 encodes
ribonucleotide reductase important for DNA
replication & repair
 Interacts with AP endonuclease & DNA
polymerase

15. MECHANISM OF P53

16. p53 Gene
 P53 can lost its function by:
Non-sense mutation or mis-sense mutation
Complex of normal p53 and mutant p53
inactivating the function of normal allele
Binding of normal p53 to viral oncoproteins

17. Role of p53 in cells with damaged DNA

18. Li- Fraumeni syndrome
 Li- Fraumeni syndrome (LFS) is a hereditary
cancer predisposition syndrome.
 This means that a person who has LFS will
have an increased risk of developing cancer.

19. Li- Fraumeni syndrome
 Common type of cancer found in LFS- bone
cancer,breast cancer, brain cancer
 Affected individuals Carry germ line mutation
in one p53 allele, but tumors display mutation
at both alleles
 Another example of two-hit hypothesis

20. APC Gene
 Implicated in familial adenomatous polyposis
coli and most sporadic colorectal cancers
 β-catenin- is a dual function protein, tissue
formation & helps to control the
acticity(expression) of other gene & promote
cell growth & division.
 In humans, β-catenin is encoded by the
CTNNB1 gene

21. APC Gene
 Excess of β-catenin promotes uncontrolled
growth & division of cells
 APC binds to and inhibits the function of
β-catenin
 Mutant APC is unable bind β-catenin to down
regulate its activity & produce desmoid tumor

22. WT-1 gene
 WT1(Wilms tumor 1)gene codes for protein
responsible development of the kidney and
gonads
 It codes for a DNA-binding protein that
represses transcription of PDGF and IGF-I
which promotes growth

23. WT-1 gene
 WT1 protein regulates the activity of other
genes by binding to specific regions of DNA
that is why it is also called transcription factor
 It also causes self-destruction of cells
(apoptosis)
 Loss of WT-1 gene expression also occur in
many breast cancers

24. NF-1 gene
 Germ line mutation in type 1
neurofibromatosis (NF)
 Encode neurofibromin, a negative regulator
of ras gene
 Inactivation of NF-1 permits unopposed ras,
thereby promotes cell growth

25. P15 and p16 genes
 Inactivation identified primarily in breast,
pancreas and prostate tumors.
 The gene products are cdk inhibitors and
serve as the negative regulators of the cell
cycle

26. BRCA1 and BRCA2 genes
 Breast (BR) cancer (CA) susceptibility genes,
also incriminated in some ovarian cancers
 Involved in G1 check point
 Block entry of cell into S phase, particularly by
inducing CDK inhibitor p21
 Promote DNA repair by binding to RAD51

27. Conclusion
 suppression of genes that are essential for the
continuing of the cell cycle.
 If the damage cannot be repaired, promote
apoptosis.
 Produce protein responsible for inhibition of
metastasis
 Inactivation of tumour suppressor gene
causes tumour

28. References
 www.bioinformatics.org/p53/introduction.html.
 www.ncbi.nlm.nih.gov/podmed/12060387
 www.nlm.nih.gov/geneAPC
 www.nlm.nih.gov/gene/NF1
 www.wikipedia.org/wiki/Neoplasm