ID4 Regulates Transcriptional Activity of Wild Type and Mutant p53 via K373 Acetylation
Morton, Derrick, Clark Atlanta University Patel, Divya, Clark Atlanta University Joshi, Jugal, Clark Atlanta University Hunt, Aisha, Clark Atlanta University Knowell, A. E., South Carolina State University Chaudhary, Jaideep, Clark Atlanta University
2016-11-29
2010-2019
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.
text
application/pdf
articles
Oncotarget
Clark Atlanta University
10.18632/oncotarget.13701
http://hdl.handle.net/20.500.12322/cau.ir:2016_chaudhary_etal
http://rightsstatements.org/vocab/InC/1.0/