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Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1779-84. doi: 10.1073/pnas.1410723112. Epub 2015 Jan 26.

p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner.

Author information

1
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara 44121, Italy;
2
Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), 34012 Trieste, Italy;
3
Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw 02-093, Poland;
4
Department of Physics and Astronomy, University of Padua, Padua 35129, Italy; Venetian Institute of Molecular Medicine, Padua 35129, Italy;
5
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy;
6
Dulbecco Telethon Institute, Istituto di Ricerche Farmacologiche Mario Negri, Milan 20156, Italy;
7
Cancer Genetics Program, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Dipartimento di Scienze della Vita, Univeristà degli Studi di Trieste, 34128 Trieste, Italy.
8
Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), 34012 Trieste, Italy; Dipartimento di Scienze della Vita, Univeristà degli Studi di Trieste, 34128 Trieste, Italy.
9
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara 44121, Italy; pnp@unife.it.

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 (Ca(2+)) 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(2+) homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca(2+)-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca(2+) load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca(2+) 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(2+) signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca(2+) signal-dependent apoptosis.

KEYWORDS:

apoptosis; calcium; endoplasmic reticulum; mitochondria-associated membranes; p53

PMID:
25624484
PMCID:
PMC4330769
DOI:
10.1073/pnas.1410723112
[Indexed for MEDLINE]
Free PMC Article

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