p53 at the endoplasmic reticulum regulates apoptosis in a Ca super( 2+)-dependent manner

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 6; p. 1779
• Main Authors: Giorgi, Carlotta, Bonora, Massimo, Sorrentino, Giovanni, Missiroli, Sonia, Poletti, Federica, Suski, Jan M, Ramirez, Fabian Galindo, Rizzuto, Rosario, Di Virgilio, Francesco, Zito, Ester, Pandolfi, Pier Paolo, Wieckowski, Mariusz R, Mammano, Fabio, Del Sal, Giannino, Pinton, Paolo
• Format: Journal Article
• Language: English
• Published: 01.02.2015
• ISSN: 0027-8424

The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death programs within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca...) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains between the ER and mitochondria (mitochondria-associated membranes). We demonstrate that, upon stress stimuli, WT p53 accumulates at these sites and modulates Ca... homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca...-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca... load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca... overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca... signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca... signal-dependent apoptosis. (ProQuest: ... denotes formulae/symbols omitted.)