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p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner
Sunday, 2015/02/15 | 05:33:48

Carlotta Giorgi, Massimo Bonora, Giovanni Sorrentino, Sonia Missiroli, Federica Poletti, Jan M. Suski, Fabian Galindo Ramirez, Rosario Rizzuto, Francesco Di Virgilio, Ester Zito, Pier Paolo Pandolfi, Mariusz R. Wieckowski, Fabio Mammano, Giannino Del Sal, and Paolo Pinton

 

Significance

Accumulating evidence has underscored the role of cytosolic p53 in promoting cell death. Different reports have revealed that p53 participates in apoptosis induction by acting directly at mitochondria. However, because p53 can mediate apoptosis without its DNA-binding domain (the domain proposed to be fundamental for the targeting of p53 to mitochondria), the mitochondrial localization of p53 is likely not the only transcription-independent mechanism by which p53 promotes apoptosis. Here we demonstrate that p53 at the endoplasmic reticulum (ER) and at mitochondria-associated membranes, interacting with sarco/ER Ca2+-ATPase pumps, modulates ER–mitochondria cross-talk and, in turn, Ca2+-dependent apoptosis.

Abstract

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 (Ca2+) 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 Ca2+ homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca2+-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca2+ load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca2+ 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 Ca2+ signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca2+ signal-dependent apoptosis.

 

See: http://www.pnas.org/content/112/6/1779.abstract.html?etoc

PNAS February 10, 2015 vol. 112 no. 6 1779-1784

 

Fig. 1.

Fig. 1. p53 localizes at the ER and MAMs. (AC) Detection of p53 by immunoblotting in HCT-116 p53+/+ fractions. (A) p53 localization in untreated condition (UNT). Accumulation of p53 at the ER and MAMs in HCT-116 p53+/+ cells after adriamycin (ADRIA) induction (1 μM, 6 h) (B) or after H2O2 treatment (500 μM, 6 h) (C). (DF) Colocalization of p53 (red) and Sec61-GFP (used as ER marker; green) in p53+/+ MEFs under untreated conditions (UNT) (D) and after ADRIA (E) or H2O2 (F). (Insets) A higher magnification of the images is presented. (G) p53 activation increased its ER colocalization. Colocalization of p53 and ER in p53+/+ MEFs quantified as the proportion of total ER marker overlapping the p53 signal (by Mander’s coefficient colocalization method). To allow for a better appreciation of colocalization of p53 with the ER, a cytoplasmic portion was selected and the contrast was increased. Bars, SEM; *P < 0.05.

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