Oncotarget

Research Papers:

ID4 regulates transcriptional activity of wild type and mutant p53 via K373 acetylation

Derrick J. Morton, Divya Patel, Jugal Joshi, Aisha Hunt, Ashley E. Knowell and Jaideep Chaudhary _

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Oncotarget. 2017; 8:2536-2549. https://doi.org/10.18632/oncotarget.13701

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Abstract

Derrick J. Morton1, Divya Patel1, Jugal Joshi1, Aisha Hunt1, Ashley E. Knowell2, Jaideep Chaudhary1

1Department of Biology, Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, GA 30314, USA

2Department of Bioengineering Sciences, South Carolina State University, Orangeburg, SC 29117, USA

Correspondence to:

Jaideep Chaudhary, email: [email protected]

Keywords: ID4, bHLH, p53, mutant-p53, tumor suppressor

Received: July 22, 2016     Accepted: November 21, 2016     Published: November 29, 2016

ABSTRACT

Given that mutated p53 (50% of all human cancers) is over-expressed in many cancers, restoration of mutant p53 to its wild type biological function has been sought after as cancer therapy. The conformational flexibility has allowed to restore the normal biological function of mutant p53 by short peptides and small molecule compounds. Recently, studies have focused on physiological mechanisms such as acetylation of lysine residues to rescue the wild type activity of mutant p53. Using p53 null prostate cancer cell line we show that ID4 dependent acetylation promotes mutant p53 DNA-binding capabilities to its wild type consensus sequence, thus regulating p53-dependent target genes leading to subsequent cell cycle arrest and apoptosis. Specifically, by using wild type, mutant (P223L, V274F, R175H, R273H), acetylation mimics (K320Q and K373Q) and non-acetylation mimics (K320R and K373R) of p53, we identify that ID4 promotes acetylation of K373 and to a lesser extent K320, in turn restoring p53-dependent biological activities. Together, our data provides a molecular understanding of ID4 dependent acetylation that suggests a strategy of enhancing p53 acetylation at sites K373 and K320 that may serve as a viable mechanism of physiological restoration of mutant p53 to its wild type biological function.


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