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.
Highlights
The somatic p53 missense mutations observed in almost half of all human cancers is a critical step in the oncogenic process [1, 2]
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, regulating p53-dependent target genes leading to subsequent cell cycle arrest and apoptosis
Wild type p53 consists of unfolded regions with high tendency for aggregation [12, 13] Numerous studies of mutant p53 have been designed to explore whether the DNA binding capacity can be restored artificially by small molecules which can stabilize the interaction with DNA, by preventing misfolding or aggregation, site-specific phosphorylation and c- terminal amino acid substitution that mimics wild type p53 [2, 14,15,16]
Summary
The somatic p53 missense mutations observed in almost half of all human cancers is a critical step in the oncogenic process [1, 2]. Wild type p53 consists of unfolded regions with high tendency for aggregation [12, 13] Numerous studies of mutant p53 have been designed to explore whether the DNA binding capacity can be restored artificially by small molecules which can stabilize the interaction with DNA, by preventing misfolding or aggregation, site-specific phosphorylation and c- terminal amino acid substitution that mimics wild type p53 [2, 14,15,16]. The binding of www.impactjournals.com/oncotarget small molecules such as CP-31398 [19], ellipticine [20], MIRA-1 [21, 22], RITA [22], and PRIMA-1 [23] to mutant p53 proteins may induce wild type like conformational changes in the DNA binding domains of p53 mutant proteins, restoring sequence-specific p53 transcription [24]. The mechanisms of activation is less understood, which provides a physiological basis of exploration into this phenomenon
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