p53, the Cellular Gatekeeper for Growth and Division

As the tale of p53 unfolds, it becomes ever more intriguing. Although our understanding of the critical and complex roles played by p53 is progressing rapidly, new findings continue to pose new paradoxes. Here we present some of these recent advances in p53 research and discuss how they either shed light on or add to the complexities of p53. Therefore, we only briefly summarize some of the key developments leading to our current state of knowledge. For further information, the reader is referred to several excellent reviews that have focused on p53 research (see Donehower and Bradley 1993; Levine 1993; Greenblatt et al. 1994; Oren 1994; Prives 1994; Kinzler and Vogelstein 1996).

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p53: puzzle and paradigm.

Tumor spectrum analysis in p53-mutant mice.

In the past fifteen years, it has become apparent that tumour-associated p53 mutations can provoke activities that are different to those resulting from simply loss of wild-type tumour-suppressing p53 function. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Here we highlight some of the emerging molecular mechanisms through which mutant p53 proteins can exert these oncogenic functions.

p53 mutations in cancer

The crucial differences between normal cells and cancer cells stem from discrete changes in specific genes controlling proliferation and tissue homeostasis. Over 100 such cancer-related genes have been discovered, several of which are implicated in the natural history of human cancer because they are consistently found to be mutated in tumors. The p53 tumor-suppressor gene is the most striking example because it is mutated in about half of almost all types of cancer arising from a wide spectrum of tissues. Other tumor-suppressor genes important in human cancers, such as adenomatous polyposis coli, Wilms' tumor type 1, and neurofibromatosis type 1, . . .

Clinical implications of the p53 tumor-suppressor gene

We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS-2 cells). Also, mutant human p53 alleles, unlike the wild-type p53 protein, could also enhance the expression of a test gene regulated by the multi-drug resistance enhancer-promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.

Shelley Chu

Papers

Gain of function mutations in p53.