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Tumor Suppressor Genes

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What are tumor suppressor genes?

Repression of genes that are essential for the cell cycle.

continuing of the

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

Gatekeep ers p53

Transcription factor

Li-Fraumeni syndrome

Caretakers

Rb1

APC

BRCA DNA repair

1

Transcriptional regulator

Regulates βcatenin function

Familial retinoblastoma

Familial adenomatus polyposis

Breast and ovarian cancer

BRCA DNA repair

2

Breast cancer(female and male)

MSH2 DNA mismatch Hereditary non-

Also mutated in 50% of human cancers

Often mutated in other cancers

Often mutated in sporadic colorectal cancers

Rarely mutated in sporadic breast cancers

Mutation permits

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

Mutated in most of the cancer cases

Normal functions p53

17

➢ It can activate damage.

DNA repair proteins when DNA has sustained

➢ It can arrest growth by holding the cell cycle at the point

G1/S regulation 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

syndrome

Multiple hamartoma

Cowden

Increased risk of cancers of the breast, thyroid and endometrium

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