Acetylation is indispensable for p53 activation.

By Yi Tang, Wenhui Zhao, Yue Chen, Yingming Zhao, W. Gu. Cell, 2008

864 citations recorded by the source corpus.

The activation of the tumor suppressor p53 facilitates the cellular response to genotoxic stress; however, the p53 response can only be executed if its interaction with its inhibitor Mdm2 is abolished. There have been conflicting reports on the question of whether p53 posttranslational modifications, such as phosphorylation or acetylation, are essential or only play a subtle, fine-tuning role in the p53 response. Thus, it remains unclear whether p53 modification is absolutely required for its activation. We have now identified all major acetylation sites of p53. Although unacetylated p53 retains its ability to induce the p53-Mdm2 feedback loop, loss of acetylation completely abolishes p53-dependent growth arrest and apoptosis. Notably, acetylation of p53 abrogates Mdm2-mediated repression by blocking the recruitment of Mdm2 to p53-responsive promoters, which leads to p53 activation independent of its phosphorylation status. Our study identifies p53 acetylation as an indispensable event that destabilizes the p53-Mdm2 interaction and enables the p53-mediated stress response.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/cbf654298c23ef6aadc2b332c98e986f0f034158

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Citations in the corpus

The world of protein acetylation. (2016, background): “p53 acetylation at these sites completely abolish the binding to p21 as well as the interaction with its repressor Mdm2, thus leading to transcriptional activation of p53-responsive genes and cell growth arrest [257].”
p53 polymorphisms: cancer implications (2009, background): “Numerous stress sensors that converge at p53 result in the phosphorylation, acetylation, ubiquitylation and methylation of specific p53 residue”
Acetyl coenzyme A: a central metabolite and second messenger. (2015, background): “TP53 is a key regulator of homeostasis in physiological and pathological conditions, and its activity is controlled by several posttranslational modifications, including acetylation at multiple (at least seven) lysine residues (Tang et al., 2008).”
The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. (2016, background): “Instead, p53 acetylation regulates p53–MDM2 interaction and recruitment of MDM2 to DNA, suggesting a more complex mechanism that needs further investigation (Tang et al. 2008).”
p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept (2016, background): “Acetylation of the DBD-located lysines generates different outputs, with Lys120 acetylation leading to the activation of genes related to apoptosis but not to cell cycle arrest, and with the acetylation of Lys164 resulting in activation of the majority of p53 target genes [213].”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “Amongst them, p53 can be subjected to a range of post-transcriptional changes that include phosphorylation (Atadja et al., 1995; Webley et al., 2000) and acetylation (Tang et al., 2008).”
Blinded by the Light: The Growing Complexity of p53. (2009, background): “Ectopically overexpressed Mdm2 (and MdmX) can bind to several other p53 target promoters, with the exception of the Mdm2 promoter itself (Tang et al., 2008).”
Tumor suppression in the absence of p53-mediated cell cycle arrest, apoptosis, and senescence (2012, neutral): “(corresponding to K161 of mouse p53) is critical for p53mediated cell-cycle arrest (Tang et al., 2008).”
Histone Deacetylase Inhibitors as Anticancer Drugs (2017, background): “Moreover, the p53 protein interactions with its activators ASPPs (Ankyrin-repeat-, SH3-domain- and proline-rich region containing proteins), 53BP1 (p53-binding protein), TiP60/hMOF (Human males absent on the first), hCAS/CSE1L (Cellular apoptosis susceptibility protein), and HZF (Hematopoietic zinc ”