Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation
Introduction
p53 is often referred to as the ‘cellular gatekeeper’ or the ‘guardian of the genome’ and its importance is emphasized by the discovery of mutations of p53 in over 50% of all human tumors [1]. p53 functions diligently and faithfully by responding to constant bombardment with genotoxic stress for the life span of the cell; whether causing cell cycle arrest, apoptosis, cellular senescence or differentiation, p53 imparts its anti-proliferative effects through a variety of mechanisms.
p53 can be thought of as a critical ‘node’ of the cellular circuitry [2]. It is here where countless signaling pathways converge, from normal everyday operations (e.g. response to growth factors) to abnormal oncogenic stimuli (e.g. response to Myc). The activity of p53 as a sequence-specific transcription factor is highly regulated by post-translational modifications, protein–protein interactions and protein stabilization. The regulation of protein stabilization is most critical upon the first indication of genotoxic stress. Cellular mechanisms for the rapid accumulation, stabilization and deployment of p53 as a potent transcription factor are imperative for preventing the growth of a damaged cell. As soon as it is sufficiently stabilized, p53 has several options at its disposal, and it is becoming more apparent that additional factors help p53 to choose a particular cell response [3].
This review will focus on recent advances made in the elucidation of the initial p53 response: namely the stabilization and transcriptional activation of p53. Because of the magnitude of advances made in this field, and the brevity required of this article, we are forced to cite many review articles. We apologize in advance to all authors making important findings in this field who are not cited.
Section snippets
Stabilizing p53
The stabilization of p53 in cells experiencing stress is crucial for their homeostasis. Mouse double minute 2 (Mdm2), the predominant negative regulator of p53, normally maintains p53 at low levels within the cell. Mdm2 acts as a specific E3 ligase for p53 by adding ubiquitin chains under normal conditions. The importance of Mdm2 to this process is underscored by the variety of mechanisms used by the cell to disrupt it in response to stress. Post-translational modifications to p53 and Mdm2,
Activating p53
In addition to stabilization, transcriptional activation of p53 is critical for initiating an early response to genotoxic stress. p53 has an arsenal of target genes at its disposal and may even possess some selectivity towards a particular fate. For example, with the assistance of ASPP proteins, p53 exhibits a striking preference for the promoters of proapoptotic genes [47••]. However, the initial activation of its function as a transcription factor is key for its ability to drive particular
Conclusions
Recent advances in understanding the initial accumulation and activation of p53 have added a layer of complexity to this pathway. The number of mechanisms used to quell p53 ubiquitination implicates this process as a key target in the initial response to genotoxic stress. Of particular interest are the specific fates of mono-ubiquitinated and poly-ubiquitinated forms of p53. Is Mdm2 sufficient for p53 degradation or are other factors required? There may be differential consequences for p53
Update
Recent work has further demonstrated the intricate link between acetylation and ubiquitination for p53 stability and function. Acetylation of p53 can inhibit p53 ubiquitination in vivo not only at acetylated lysine residues but also at unacetylated residues [83]. This finding suggests that, in addition to acetylation directly blocking ubiquitination at specific residues, it may also attenuate ubiquitination of other unacetylated lysine residues by inducing a protein conformational change.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
We thank members of the Gu laboratory for sharing critical comments of the manuscript. This work was supported in part by a National Institutes of Health training grant (5-T32-CAO9503-17) to CLB; by grants from the Avon Foundation, the Stewart Trust, the Irma T Hirschl Trust, and National Institutes of Health/National Cancer Institute to WG, who is also a Leukemia and Lymphoma Society Scholar.
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