Tax Mediated Inhibition of p53 Mediated Cell Cycle Arrest and Apoptosis

The p53 protein is perhaps the principal cell cycle regulator.70,71 If there are recognizable mutations after S phase, the concentration of p53 in the nucleus will increase. p53 and the CREB-binding protein (CBP) form a dimer capable of binding to the enhancers of p53 responsive genes. This results in the synthesis of the cyclin-dependent kinase inhibitor p21, cell surface receptor Fas, and the cytoplasmic protein Bax. The presence of p21 results in cell cycle arrest, permitting time for DNA repair so that the mutations do not become permanently etched in the genome. If the damage is irreparable, the increasing levels of Fas surface expression and cytoplasmic Bax renders the cell vulnerable to apoptotic signaling and, ultimately, induces apoptosis.

In order to mediate its trans-activating properties, Tax must associate with CBP.72,73 Tax acts as a competitive inhibitor of the p53/CBP binding event by binding to the same protein folding domain of CBP as p53.74-76 The effects of Tax on the p53 pathway of tumor suppression are summarized in Figure 12-11. The presence of Tax trans-suppresses p53 responsive genes, and protects the cell from both cell cycle arrest and p53 induced apoptosis.

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