Genetics

Tumor Suppressor Gene

Tumor-suppressor genes generally encode proteins that in one way or another inhibit cell proliferation. Loss-offunction mutations in one or more of these “brakes” contribute to the development of many cancers. Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes:

The p53 gene encodes the tumor suppressor protein, p53. A tumor suppressor has a negative effect on cell growth and division. p53 protein functions in many different pathways in the cell; one important function is described here. The p53 gene is expressed to produce the p53 protein. In a normal cell, that protein is unstable so the amount of p53 protein in the cell is small. If lesions are introduced into DNA, the p53 protein is stabilized by a mechanism that is not currently understood. This leads to an increase in the amount of p53 protein in the cell.

 

p53 then binds to the promoter of gene WAF1 and activates the expression of that gene. The product is a protein called p21. p21 now has an effect on the cell cycle. For a cell to progress from G1 to S, one or G1 cyclin proteins bind to the enzyme cyclin-dependent kinase (Cdk) and activates it. The Cdk then phosphorylates key proteins needed for progression of the cell into S. When p21 is present, it binds to the cyclin-Cdk complex, blocking kinase activity. The absence of kinase activity prevents the transition of the cell into S and it arrests in G1 phase and dies. This programmed cell death is called apoptosis.

 

If both alleles of p53 are inactivated in the cell, none of the tumor suppressor p53 is present to activate the WAF1 gene, and no p21 is made. Cdk activity is nor blocked, so the cell cannot be arrested in G1 phase, and the cell will proceed into S phase rather than undergo apoptosis. The progression of cells with DNA damage through the cell cycle can cause cells to accumulate additional mutations and hence increase the probability cancer.

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