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 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 β-catenin function

Familial adenomatus polyposis

Often mutated in sporadic colorectal cancers

Caretakers

BRCA1

DNA repair Breast and ovarian cancer

Rarely mutated in sporadic breast cancers

BRCA2

DNA repair Breast cancer(female and male)

MSH2MLH1

DNA mismatch repair

Hereditary non-polyposis colorectal cancer

Mutation permits further mutations (‘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 metastasisGerm line mutation responsible for

Cowden syndrome Multiple hamartoma Increased risk of cancers of the breast, thyroid and endometrium