PML regulates apoptosis at endoplasmic reticulum by modulating calcium release

The promyelocytic leukemia (PML) tumor suppressor is a pleiotropic modulator of apoptosis. However, the molecular basis for such a diverse proapoptotic role is currently unknown. We show that extranuclear Pml was specifically enriched at the endoplasmic reticulum (ER) and at the mitochondria-associa...

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Published in:Science (American Association for the Advancement of Science) Vol. 330; no. 6008; p. 1247
Main Authors: Giorgi, Carlotta, Ito, Keisuke, Lin, Hui-Kuan, Santangelo, Clara, Wieckowski, Mariusz R, Lebiedzinska, Magdalena, Bononi, Angela, Bonora, Massimo, Duszynski, Jerzy, Bernardi, Rosa, Rizzuto, Rosario, Tacchetti, Carlo, Pinton, Paolo, Pandolfi, Pier Paolo
Format: Journal Article
Language:English
Published: United States 26.11.2010
Subjects:
Adenosine Triphosphate - metabolism
Animals
Apoptosis
Calcium - metabolism
Calcium Signaling
Cell Line
Cell Nucleus - metabolism
Cells, Cultured
Cytosol - metabolism
Endoplasmic Reticulum - metabolism
Homeostasis
Humans
Inositol 1,4,5-Trisphosphate - metabolism
Inositol 1,4,5-Trisphosphate Receptors - metabolism
Intracellular Membranes - metabolism
Mice
Mitochondria - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Phosphorylation
Promyelocytic Leukemia Protein
Protein Phosphatase 2 - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Recombinant Fusion Proteins - metabolism
Stress, Physiological
Transcription Factors - genetics
Transcription Factors - metabolism
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary:The promyelocytic leukemia (PML) tumor suppressor is a pleiotropic modulator of apoptosis. However, the molecular basis for such a diverse proapoptotic role is currently unknown. We show that extranuclear Pml was specifically enriched at the endoplasmic reticulum (ER) and at the mitochondria-associated membranes, signaling domains involved in ER-to-mitochondria calcium ion (Ca(2+)) transport and in induction of apoptosis. We found Pml in complexes of large molecular size with the inositol 1,4,5-trisphosphate receptor (IP(3)R), protein kinase Akt, and protein phosphatase 2a (PP2a). Pml was essential for Akt- and PP2a-dependent modulation of IP(3)R phosphorylation and in turn for IP(3)R-mediated Ca(2+) release from ER. Our findings provide a mechanistic explanation for the pleiotropic role of Pml in apoptosis and identify a pharmacological target for the modulation of Ca(2+) signals.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.1189157