Fiamma Mantovani1, Alessandro Zannini1, Alessandra Rustighi1, Giannino Del Sal2. 1. Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy. 2. Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy. Electronic address: delsal@lncib.it.
Abstract
BACKGROUND: The p53 protein family, comprising p53, p63 and p73, is primarily involved in preserving genome integrity and preventing tumor onset, and also affects a range of physiological processes. Signal-dependent modifications of its members and of other pathway components provide cells with a sophisticated code to transduce a variety of stress signaling into appropriate responses. TP53 mutations are highly frequent in cancer and lead to the expression of mutant p53 proteins that are endowed with oncogenic activities and sensitive to stress signaling. SCOPE OF REVIEW: p53 family proteins have unique structural and functional plasticity, and here we discuss the relevance of prolyl-isomerization to actively shape these features. MAJOR CONCLUSIONS: The anti-proliferative functions of the p53 family are carefully activated upon severe stress and this involves the interaction with prolyl-isomerases. In particular, stress-induced stabilization of p53, activation of its transcriptional control over arrest- and cell death-related target genes and of its mitochondrial apoptotic function, as well as certain p63 and p73 functions, all require phosphorylation of specific S/T-P motifs and their subsequent isomerization by the prolyl-isomerase Pin1. While these functions of p53 counteract tumorigenesis, under some circumstances their activation by prolyl-isomerases may have negative repercussions (e.g. tissue damage induced by anticancer therapies and ischemia-reperfusion, neurodegeneration). Moreover, elevated Pin1 levels in tumor cells may transduce deregulated phosphorylation signaling into activation of mutant p53 oncogenic functions. GENERAL SIGNIFICANCE: The complex repertoire of biological outcomes induced by p53 finds mechanistic explanations, at least in part, in the association between prolyl-isomerases and the p53 pathway. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets.
BACKGROUND: The p53 protein family, comprising p53, p63 and p73, is primarily involved in preserving genome integrity and preventing tumor onset, and also affects a range of physiological processes. Signal-dependent modifications of its members and of other pathway components provide cells with a sophisticated code to transduce a variety of stress signaling into appropriate responses. TP53 mutations are highly frequent in cancer and lead to the expression of mutant p53 proteins that are endowed with oncogenic activities and sensitive to stress signaling. SCOPE OF REVIEW: p53 family proteins have unique structural and functional plasticity, and here we discuss the relevance of prolyl-isomerization to actively shape these features. MAJOR CONCLUSIONS: The anti-proliferative functions of the p53 family are carefully activated upon severe stress and this involves the interaction with prolyl-isomerases. In particular, stress-induced stabilization of p53, activation of its transcriptional control over arrest- and cell death-related target genes and of its mitochondrial apoptotic function, as well as certain p63 and p73 functions, all require phosphorylation of specific S/T-P motifs and their subsequent isomerization by the prolyl-isomerase Pin1. While these functions of p53 counteract tumorigenesis, under some circumstances their activation by prolyl-isomerases may have negative repercussions (e.g. tissue damage induced by anticancer therapies and ischemia-reperfusion, neurodegeneration). Moreover, elevated Pin1 levels in tumor cells may transduce deregulated phosphorylation signaling into activation of mutant p53 oncogenic functions. GENERAL SIGNIFICANCE: The complex repertoire of biological outcomes induced by p53 finds mechanistic explanations, at least in part, in the association between prolyl-isomerases and the p53 pathway. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets.
Authors: Alessandra Rustighi; Alessandro Zannini; Elena Campaner; Yari Ciani; Silvano Piazza; Giannino Del Sal Journal: Cell Death Differ Date: 2016-11-11 Impact factor: 15.828
Authors: R Ramírez-Patiño; G Avalos-Navarro; L E Figuera; J J Varela-Hernández; L A Bautista-Herrera; J F Muñoz-Valle; M P Gallegos-Arreola Journal: Int J Immunopathol Pharmacol Date: 2022 Jan-Dec Impact factor: 3.298
Authors: Maria Solange Ibarra; Carla Borini Etichetti; Carolina Di Benedetto; Germán L Rosano; Ezequiel Margarit; Giannino Del Sal; Marina Mione; Javier Girardini Journal: PLoS One Date: 2017-04-20 Impact factor: 3.240
Authors: Luana D'Artista; Andrea Bisso; Andrea Piontini; Mirko Doni; Alessandro Verrecchia; Theresia R Kress; Marco J Morelli; Giannino Del Sal; Bruno Amati; Stefano Campaner Journal: Oncotarget Date: 2016-04-19