Abstract
The p53 gene family members p53, p73, and p63 display several isoforms derived from the presence of internal promoters and alternative splicing events. They are structural homologs but hold peculiar functional properties. p53, p73, and p63 are tumor suppressor genes that promote differentiation, senescence, and apoptosis. p53, unlike p73 and p63, is frequently mutated in cancer often displaying oncogenic “gain of function” activities correlated with the induction of proliferation, invasion, chemoresistance, and genomic instability in cancer cells. These oncogenic functions are promoted either by the aberrant transcriptional cooperation of mutant p53 (mutp53) with transcription cofactors (e.g., NF-Y, E2F1, Vitamin D Receptor, Ets-1, NF-kB and YAP) or by the interaction with the p53 family members, p73 and p63, determining their functional inactivation. The instauration of these aberrant transcriptional networks leads to increased cell growth, low activation of DNA damage response pathways (DNA damage response and DNA double-strand breaks response), enhanced invasion, and high chemoresistance to different conventional chemotherapeutic treatments. Several studies have clearly shown that different cancers harboring mutant p53 proteins exhibit a poor prognosis when compared to those carrying wild-type p53 (wt-p53) protein. The interference of mutantp53/p73 and/or mutantp53/p63 interactions, thereby restoring p53, p73, and p63 tumor suppression functions, could be among the potential therapeutic strategies for the treatment of mutant p53 human cancers.
Highlights
P53, p73, and p63 proteins belong to a family evolutionarily conserved in animals
P73 shows a peculiar function in neuronal differentiation, not shared with p53 [8, 61]. p73 is rarely affected by mutation in cancer progression [62, 63] but its expression is deregulated in several human tumors, such as in hepatocellular carcinoma [64], neuroblastoma [65], lung cancer [62], prostate cancer [66] and colorectal carcinoma [67]. p73 shares many p53 tumor suppression functions through the activation of the p53-target genes (p21waf1, Bax, PUMA, NOXA, IGF-BP3 and Cyclin G), resulting in the control of cell proliferation, differentiation, development and induction of apoptosis [68,69,70,71,72,73,74,75,76,77,78,79]
Flores et al [164] demonstrated that wt-p53, p73 and p63 are recruited onto regulatory regions of the p53-target genes inducing growth arrest, differentiation, senescence and apoptosis (Figure 2)
Summary
P53, p73, and p63 proteins belong to a family evolutionarily conserved in animals. They derive from an ancestral gene by duplication and consequent divergence of the original sequence. Weissmueller et al [141] confirm that mutant p53 is able to bind p73 and this interaction results in the reduction of p73/ NF-Y inhibitory complex in pancreatic ductal adenocarcinoma This complex displays a tumor suppressor function repressing the oncogenic platelet-derived growth factor receptor b (PDGFRb) that promotes cell invasion and metastasis. It is worth to mention the role of MDM2 in the mutp, p63, and p73 interplay: a recent work shows that MDM2, a negative regulator of wt-p53, competes with p63 for binding to mutp53R175H and in this way p63 activity is restored; but, on the other hand, MDM2 forms a trimeric complex with p73 and mutp53R273H strongly inhibiting p73 function [144] All these are clear examples of how different mutations in p53 protein could determine distinct protein–protein interactions and cell responses. Recently it is discovered that a small molecule, NSC59984, can restores wt-p53 signaling via p73 activation and induces p73-dependent cell death in colorectal cancer cells, without evident toxicity toward normal cells [181]
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