Some p53-binding proteins that can function as arbiters of life and death

Abstract

Four sets of p53-binding proteins are discussed in this review. These are the E2F family, the ASPP family, Y-boxbinding protein YB1, and the prolyl isomerase Pin1. Each appears to play a role in the decision by p53 to induce an arrest of cell proliferation or apoptosis and they may also be independent markers of cancer. Their activities appear to be linked with the cell cycle and they may also interact with each other. In this review, the properties of each protein class are discussed as well as how they affect p53 functions. A model is proposed as to how their activities might be coordinated.

The dark side of a tumor suppressor: anti-apoptotic p53

“…Assuming for example that p53 itself plays no role in determining the cellular stress response, a 'dumb' p53 might always send the same signals after activation, including induction of pro-and anti-apoptotic genes. 172 In this case, the outcome of a p53 activation might depend on the availability of the afore mentioned cofactors regulating even a tissue-specific expression of genes, 123 as it was observed for instance with Slug and 14-3-3 that are predominantly expressed in hematopoietic progenitor and epithelial cells, respectively. Also different promoter strengths of pro-versus anti-apoptotic genes might then be crucial; however, no definite correlation between promoter binding and apoptosis induction has yet been established.…”

“…Clearly, several co-factors can selectively modulate p53 transcription and these factors are most likely set in place by a multitude of conditions including cellular context as well as type, strength and duration of a stimulus that are known to critically determine the fate of a cell. 10,123 However, exactly how these conditions impose on p53 and stimulate partially opposing pathways is mostly beyond our knowledge. Trying to accommodate as much of the overwhelming information as possible, several models were suggested to explain the trouble we have with the decisionmaking process of p53.…”

“…While such a regulation is clearly important, p53 protein levels are not the sole regulatory control on p53 function that most likely depends also upon cofactors that enhance or repress the DNA binding or transactivation functions of p53. 123 Intriguingly, p53 regulates expression of several p53-binding proteins that in turn negatively interfere not only with its own stabilization and activation, but also with regard to its transactivation function.…”

“…Over the past few years several p53-interacting proteins were identified that were shown to modulate the transcriptional activity of p53. 10,123 Except for a postulated p53-mediated repression of the pro-apoptotic p53-binding protein-2 (53BP2), expression of these proteins is currently assumed not to be regulated by p53. In contrast, the hematopoietic zinc finger protein (Hzf) was reported to be a direct target of p53 in NIH-3T3 cells that contributes to the maintenance of the G2 checkpoint and survival upon induction by DNA damage.…”

Ubiquitin-independent p53 proteasomal degradation

“…34 There are many proteins that interact with p53. 35,36 According to Genecards (http://www.genecards.org), there are more than 639 p53 interacting proteins. Most of the interacting proteins of p53 bind the unstructured N-or C-terminus.…”