1. Tumor Suppressor Genes

2. What are tumor suppressor genes?
Repression of genes that are essential for the continuing of the
cell cycle.
Coupling the cell cycle to DNA damage. As long as there is
damaged DNA in the cell, it should not divide.
If the damage cannot be repaired, the cell should
initiate apoptosis (programmed cell death)
Some proteins involved in cell adhesion prevent tumor cells from
dispersing, block loss of contact inhibition, and inhibit metastasis.
These proteins are known as metastasis suppressors

3. 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

4. Tumor suppressor genes: functional categories and tumor
association
Category Gene Function Tumor susceptibility
if germ line
mutation
Comments
Gatekeep
ers
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 β-
catenin function
Familial
adenomatus
polyposis
Often mutated in
sporadic colorectal
cancers
Caretaker
s
BRCA
1
DNA repair Breast and ovarian
cancer
Rarely mutated in
sporadic breast
cancers
BRCA
2
DNA repair Breast
cancer(female and
male)

5. 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, remaining ones are familial

6. Two-hit hypothesis
 To account for the sporadic and familial occurrence of
retinoblastoma, Knudson, in 1971
– 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.

7. The “two-hit" origin of retinoblastoma

8. p53 Gene
 Situated at the short arm of the chromosome 17
 Mutated in most of the cancer cases
 Normal functions p53
 It can activate DNA repair proteins when DNA has sustained
damage.
 It can arrest growth by holding the cell cycle at the G1/S regulation
point on DNA damage recognition (if it holds the cell here for long
enough, the DNA repair proteins will have time to fix the damage and
the cell will be allowed to continue the cell cycle).
 It can initiate apoptosis, the programmed cell death, if DNA damage
proves to be irreparable.

9. 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”

10. 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

11. Role of p53 in cells with damaged DNA

13. Li-Fraumeni syndrome
 Refers to the inherited predisposition to develop cancers in many organs
owing to germ line mutations of p53
 Affected individuals Carry germ line mutation in one p53 allele, but
tumors display mutation at both alleles
 Another example of two-hit hypothesis

14. Other tumor suppressor genes

15. APC Gene
 Implicated in familial adenomatous polyposis coli and most
sporadic colorectal cancers
 APC binds to and inhibits the function of β-catenin
 β-catenin activates certain transcription factors that activates
several genes including myc and cyclin D
 Mutant APC is unable bind β-catenin to down regulate its activity

16. WT-1 gene
 Is deleted in hereditary Wilms tumor(WT)
 It codes for a DNA-binding protein that represses transcription of
PDGF,IGF-I and abl2, which promotes growth
 Loss of WT-1 gene expression also occur in many breast cancers

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

18. von Hippel-Lindau (VHL) gene
 Inactivation results in VHL syndrome, which is associated with
renal cell carcinoma, hemangioblastoma of the brain,
pheochromocytoma
 Normal VHL protein complexes with and inhibit elongin,a molecule
that promotes transcriptional elongation of growth promoting
genes

19. 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

20. BRCA1 and BRCA2 genes
 Brest(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

21. PTEN gene
Termed phosphatase and tensin homologue
Mutated in most prostate cancers and many
glioma and thyroid cancers
The gene product suppresses tumor growth by
antagonising tyrosine kinases
Regulates invasion and metastasis
Germ line mutation responsible for Cowden
syndrome
 Multiple hamartoma
 Increased risk of cancers of the breast, thyroid and endometrium