title: ID4 regulates transcriptional activity of wild type and mutant p53 via K373 acetylation.
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.
authors.affiliation: Department of Biology, Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, GA 30314, USA.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Morton
authors.affiliation: Department of Biology, Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, GA 30314, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Biology, Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, GA 30314, USA.
authors.forename: Jugal
authors.initials: J
authors.lastname: Joshi
authors.affiliation: Department of Biology, Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, GA 30314, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Hunt
authors.affiliation: Department of Bioengineering Sciences, South Carolina State University, Orangeburg, SC 29117, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Knowell
authors.affiliation: Department of Biology, Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, GA 30314, USA.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Chaudhary
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008239:Lysine
keywords: ID4; bHLH; mutant-p53; p53; tumor suppressor