Dynamics of the p53 acetylation pathway

Wei Gu, Jianyuan Luo, Chris L. Brooks, Anatoly Y. Nikolaev, Muyang Li, Baylin, Turner, Pelicci, Mahadevan

Research output: Contribution to journalArticlepeer-review

Abstract

The p53 tumour suppressor exerts anti-proliferative effects, including growth arrest, apoptosis and cell senescence, in response to various types of stress. However, p53 is a short-lived protein and its activity is maintained at low levels in normal cells. Numerous studies indicate that CBP/p300-mediated acetyl-transferase activity is critical for its role in both catalysing p53 acetylation and activating p53-mediated function during stress response. Interestingly, two additional regulators have also been identified in the p53 acetylation pathway. PID/MTA2 is a p53-interacting protein that induces p53 deacetylation by recruiting the HDAC1 complex. Subsequent work has also identified Sir2α, a NAD-dependent histone deacetylase that can attenuate p53 transcriptional activity through deacetylation. The prominence of deacetylase activity on p53 certainly raises the defining question of its physiological purpose. It is likely that deacetylation provides a quick acting mechanism to stop p53 function once transcriptional activation of target genes is no longer needed. We present data indicating that both HDAC1 and Sir2α are critical for p53-dependent stress response. Furthermore, we also try to define the functional consequence of p53 acetylation at the molecular level. Finally, we propose a model regarding the differential roles of HDAC1 and Sir2α in the regulation of p53 function.

Original languageEnglish (US)
Pages (from-to)197-207
Number of pages11
JournalNovartis Foundation Symposium
Volume259
StatePublished - Dec 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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