Regulation and activation of p53 and its family members

Abstract

Regulation of the p53 tumor suppressor protein occurs to a large extent through control of protein stability, and the MDM2 protein has been shown to play a key role in targeting p53 for degradation. Stress signals that activate the p53 response lead to stabilization of p53 through inhibition of MDM2 mediated degradation, and it is becoming evident that a number of mechanisms exist to abrogate this activity of MDM2. Other members of the p53 protein family may also be regulated through protein stability, although MDM2 is not responsible for the degradation of p73. Nevertheless, interactions of p63 and p73 with MDM2 or p53 have been described, suggesting that each of the p53-related proteins can play some role in regulating the activity of the others Keywords: p53; p73; p63; MDM2; E2F-1; protein stability Common themes, different players: Regulation of p53, p73 and p63The tumor suppressor protein p53 has been studied intensively over the past decade, and it is clear that p53 activity plays an important role in preventing tumor development. p53 is a potent inhibitor of cell growth and so control of p53 activity is essential during normal growth and development. Regulation of p53 has been described at the level of transcription and translation, 1 and through allosteric regulation of p53 conformation. 2 However, by far the most attention has been directed to modulation of p53 protein stability which appears to be one of the critical mechanism by which p53 function is regulated, and the mechanisms through which p53 is degraded have been under intense scrutiny over the past few years. The recent identification of the p53 related proteins, p63 and p73, has raised the question of whether all the family members are regulated through the same mechanisms to allow for a coordinated response, or whether each protein is subject to independent regulation. This review aims to summarize the present models on how the p53 protein is degraded and how these pathways are inhibited to allow activation of a p53 response, with comparisons to our, as yet, less comprehensive understanding of how p73 and p63 activity is controlled.

MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis

“…Recently, it has been shown in p53 Ϫ/ ϪMDM2 Ϫ/Ϫ MEF that inhibition of the p53 transcriptional activity by MDM4 requires cooperation of MDM2, an observation that indicates that MDM4 per se is not able to exert such inhibition and indirectly supports our data (13). Moreover, since conditions that activate p53 function alleviate MDM2 binding and inhibition of p53 (3,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64), they may also alleviate MDM4 inhibitory activity. Indeed, following p53 induction by Adr, we do not observe a concomitant increase of MDM4 binding to p53, in analogy to what was reported for MDM2 (40).…”

p38 Mitogen-activated Protein Kinase Mediates Hypoxic Regulation of Mdm2 and p53 in Neurons

“…The known and proposed roles of Mdm2 in regulating p53 function suggest that the effects of hypoxia on Mdm2 and p53 may be interrelated (37). First, because binding to Mdm2 promotes the proteasomal degradation of p53 through Mdm2's action as a ubiquitin ligase (36), reduction of Mdm2 expression by hypoxia could account for the observed increase in p53 levels in our hypoxic neuronal cultures.…”

Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo

“…Mutations within the p53 tumor suppressor gene have been well documented in Ͼ50% of all human tumors (4). In cells that retain wild-type p53, multiple regulatory pathways play an important role in modulating its activities in vivo (2,5,6). p53 promotes tumor suppression through its ability to bind specific DNA sequences and to act as a transcription factor (7).…”