Tumor Suppressor Genes

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
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
Tumor suppressor genes: functional categories and tumor association
Category Gene Function Tumor susceptibility Comments
if germ line mutation

Gatekeepers p53 Transcription Li-Fraumeni Also mutated in 50% of

factor syndrome human cancers
Rb1 Transcriptional Familial Often mutated in other
regulator retinoblastoma cancers
APC Regulates β- Familial adenomatus Often mutated in
catenin function polyposis sporadic colorectal
cancers
Caretakers BRCA1 DNA repair Breast and ovarian Rarely mutated in
cancer sporadic breast
cancers
BRCA2 DNA repair Breast cancer(female
and male)
MSH2 DNA mismatch Hereditary non- Mutation permits
MLH1 repair polyposis colorectal further mutations
cancer (‘mutator phenotype’)
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

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.
The “two-hit" origin of retinoblastoma
 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.
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”

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

Role of p53 in cells with damaged DNA
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

Other tumor suppressor genes
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
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
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
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
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
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
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