Modulation of p53 function in cellular regulation

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The regulation of p53 stability and activity and its control of the cell cycle and apoptosis is central to the problem of human tumorigenesis. p53 was first described as a cellular phosphoprotein that co-precipitated with the large T antigen of simian virus 40 and whose synthesis was enhanced in chemically transformed tumors. In the last twenty years, its role in tumor suppression and in the normal cellular responses to environmental stresses has been clearly established. Its inactivation through mutations or deletions, along with loss of the wild-type allele, is correlated with over half of human tumors and is now thought to play a central role in cancer development. Much of the function of p53 occurs through its role as a transcription factor for genes that mediate DNA damage repair, growth arrest and apoptosis; however, despite extensive and intensive research into the function and structure of p53, many questions regarding the molecular mechanisms by which p53 is regulated still remain. A major area of uncertainty is the role of posttranslational modifications. Nevertheless, progress has been made, and clear evidence as to the molecular function(s) of a few modifications is emerging. New techniques are being applied with success to the study of p53 posttranslational modifications, the most important of which are: (a) the development of immunological techniques for detecting posttranslational modifications at specific sites without causing DNA damage or altering cell growth signals, (b) the development of extremely sensitive and accurate mass spectrometry methods for determining peptide mass and amino-acid sequence and (c) the development of methods for engineering embryonic stem cells to introduce specific homozygous missense mutations or combinations of mutations in the endogenous genes of mice that change posttranslational modification sites.

In the current series of minireviews, we focus on four topics where major advances are being made. The first review (Appella and Anderson) discusses the current state of knowledge of the posttranslational modifications to p53, their role in p53 stability and activity, and the enzymes that are believed to be responsible for each modification. Remarkably, 18 different sites in human p53 are reported to be posttranslationally modified, and most are modified in response to genotoxic stress. Furthermore, p53 is modified in three different ways: by phosphorylation, by acetylation, and by sumoylation. Key sites appear to be targeted by more than one signaling enzyme, and there is growing evidence that modifications to several sites are linked in cascades that may provide signal amplification and integration.

The second review, by Grossman, examines the still expanding field of p300/CBP-p53 interaction and the role of p300/CBP in regulating the p53 response. Indeed, the first indication of the existence of a p300/MDM2 complex that participates in MDM2-mediated p53 degradation was published in 1998 [1]. This report, in turn, led to the discovery that MDM2 inhibits p300-mediated acetylation and activation of p53 through formation of a p300/MDM2/p53 tripartite complex [2,3].

The third review, by Liang and Clarke, discusses the regulation of p53 cellular localization and the elements and molecules involved in p53 nucleo-cytoplasmic transport. Indeed, it has been demonstrated that p53 is subject to both nuclear import and export controls and that nuclear retention is essential for p53 function. The coordinate regulation of enhanced nuclear import and decreased nuclear export is essential in modulating the various p53 functions, and several questions regarding p53 cellular trafficking are discussed in this review.

The final contribution, by Itahana, Dimri and Campisi, considers recent advances in our understanding of the role of p53 in cellular senescence. Cellular senescence likely has evolved to suppress the development of tumors, but many questions remain as to how p53 is activated and elicits a senescence phenotype. As discussed in this review, p53 is essential for the senescence response to a variety of signaling factors and may initiate the senescence response partly through the induction of p21.

The reviews should leave readers with an appreciation of how the application of new tools are rapidly leading to a complete catalogue of p53 modifications and to an understanding of the signals that create them. Coupled with advances in methods to genetically manipulate response pathways in cells and whole animals, we stand on the threshold of a major advance in our understanding of p53 regulation.

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