New plays in the p53 theater

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The p53 tumor suppressor and its paralogs p63 and p73 are at the crux of a network modulating cellular responses against potentially tumorigenic events. p53 acts primarily as a transcription factor, regulating the expression of both coding and non-coding RNAs, as well as the activity of RNA processing complexes. In line with their anti-tumorigenic function, p53 and p63 have recently been implicated in restricting tumor cell invasion. In parallel, a growing number of non-canonical target genes have been added to the p53 repertoire. These include genes encoding for proteins that impinge on a broad spectrum of cellular functions, from cell metabolism to stem cell renewal. The p53 story is still far from being fully told.

Introduction

Humans with germline p53 mutations are affected by the Li-Fraumeni syndrome, characterized by very high cancer susceptibility [1, 2]. p53 knockout mice develop tumors with short latency and 100% penetrance [3]. In approximately 50% of human cancers p53 is mutated; in many of the remaining 50%, the function of the retained wild type (wt) p53 protein is compromised by deregulation of upstream or downstream components of the p53 pathway [4]. En masse, these observations demonstrate the critical role of p53 in tumor prevention.

In unstressed cells, p53 is constitutively restrained by Mdm2, an E3 ubiquitin ligase that promotes p53 degradation; the Mdm2 gene is positively regulated by p53, defining a negative feedback loop that controls p53 activity. Cellular stress relieves Mdm2's inhibitory effects, triggering p53 stabilization and activation. Once activated, p53 facilitates DNA repair and inhibits the proliferation of potentially tumorigenic cells, chiefly through instigating cell cycle arrest, senescence or apoptosis.

The p53 response is elicited by a wide variety of stress signals conducive to or associated with malignant transformation, such as DNA damage, oncogene activation, abnormal mitosis, loss of cell–cell contact and hypoxia [5]. Although seemingly dissimilar, many of these signals may actually converge on one another. Biochemically, p53 is a potent transcriptional regulator capable of controlling the expression of hundreds of genes [4, 5]. Within this context, it interacts with numerous cofactors and binding partners that modulate its transcriptional output. The p53 gene family includes two additional members, p63 and p73, also acting as transcriptional modulators.

The great interest in p53 has spawned numerous excellent reviews. Therefore, we will focus only on a limited set of recent studies, pertaining particularly to new functions of p53 and family.

Section snippets

p53 and metabolism

Recent years have seen a renaissance of interest in the links between cancer and metabolism; p53 research is no exception.

p53 engages in an intricate interplay with reactive oxygen species (ROS). Under conditions of mild, physiological oxidative stress, p53 preferentially induces expression of antioxidant genes; when ROS production is aberrantly high, p53 instead activates pro-oxidant genes that may facilitate apoptosis, along with overt proapoptotic genes such as PUMA, Bax and Pig3 [6].

p53 and non-coding RNAs

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate protein levels by binding to specific mRNAs, inhibiting their translation and often also accelerating their degradation. As is the case for protein-coding mRNAs, miRNA expression patterns are also grossly altered in cancer. p53 modulates the expression of numerous miRNA species, including miR-34a,b and c [17, 18]. It may not be coincidental that some of the mRNA species targeted by p53-responsive miRNAs are also directly

The p53 family and tumor cell invasion

Increased invasiveness of cancer cells is a major driver of metastasis and malignancy. This has not escaped the attention of p53 and its family member p63 (Figure 3). Loss of p53 augments cancer cell invasion [27]; conversely, p53 activation suppresses migration and invasion [28]. This inhibitory effect of p53 is partly mediated by Mdm2, which promotes the ubiquitination and degradation of Slug and Snail, pivotal transcription factors that drive tumor cell invasiveness [29, 30]. The

p53 in stem cells (SCs) and aging — two sides of the same coin?

Recently, there has been a flourish of publications demonstrating that p53 deficiency facilitates reprogramming of differentiated cells into induced pluripotent stem (iPS) cells, closely resembling embryonic stem (ES) cells [42•, 43•, 44•, 45•, 46•]. The exact nature of the antagonism between p53 and reprogramming pathways is still debated. One possibility is that the iPS procedure indirectly causes DNA damage, driving p53 to activate a barrier of anti-proliferative senescence [47, 48].

Conclusion

Since its discovery more than 30 years ago, a massive amount of data has accumulated that attests to the tumor suppressing role of p53. However, as we keep exploring the intricacies of p53 activity, more and more of its diverse functions are cropping up. The field of tumor suppression is experiencing a growing interest in «esoteric» subjects such as metabolism and SCs. Perhaps, with knowledge from this broader picture, we will also better understand the workings of cancer cells.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work in the authors’ laboratories is supported by grants from the National Cancer Institute (R37 CA40099), the Flight Attendant Medical Research Institute, the European Commission (OncomiRs, FP7 Contract 201102 and INFLACARE, FP7 Contract 223151), the Robert Bosch Foundation, and the M.D. Moross Cancer Institute. M.O. is the incumbent of the Andre Lwoff Professorial Chair in Molecular Biology at the Weizmann Institute.

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