Cell cycle regulation and the p53 tumor suppressor protein

Somatic mutations of the p53 gene have been implicated as causal events in the formation of a large number of common human tumors. Several lines of evidence suggest that the nuclear phosphoprotein encoded for by the wild-type gene (wt-p53) plays a role in regulating cell proliferation. Wt-p53 protein encodes a potent negative growth regulatory function that is lacking in mutant forms of the protein found in human tumors. In this review, the relationship between the expression of wt-p53 protein and cell proliferation is examined with emphasis on recent studies that provide clues as to the possible role that p53 plays in cell cycle regulation. A model for the action of p53 in regulating cell proliferation is proposed in which wt-p53 acts as a "checkpoint" protein to control the transit of cells through the restriction point in late G1-phase. After cells pass this "checkpoint" they become committed to enter S-phase and initiate DNA replication. This checkpoint function may be defective in cells that lack p53, express mutant p53, or in which the antiproliferative form of the protein is functionally inactive. Under these conditions stringent control of the initiation of DNA replication may no longer be possible, providing an environment conducive to the emergence oncogenic clones.