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Science 330 (6008): 1247-1251

Copyright © 2010 by the American Association for the Advancement of Science

PML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release

Carlotta Giorgi,1,2,3,4 Keisuke Ito,3,4 Hui-Kuan Lin,4 Clara Santangelo,5 Mariusz R. Wieckowski,6 Magdalena Lebiedzinska,6 Angela Bononi,1 Massimo Bonora,1 Jerzy Duszynski,6 Rosa Bernardi,3,4,7 Rosario Rizzuto,8 Carlo Tacchetti,5,9 Paolo Pinton,1,3,4,* Pier Paolo Pandolfi3,4,*

Abstract: 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 (Ca2+) transport and in induction of apoptosis. We found Pml in complexes of large molecular size with the inositol 1,4,5-trisphosphate receptor (IP3R), protein kinase Akt, and protein phosphatase 2a (PP2a). Pml was essential for Akt- and PP2a-dependent modulation of IP3R phosphorylation and in turn for IP3R-mediated Ca2+ 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 Ca2+ signals.

1 Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Emilia Romagna Laboratory BioPharmaNet, and Laboratory for Technologies of Advanced Therapies (LTTA) University of Ferrara, Ferrara, Italy.
2 Vita-Salute San Raffaele University, Center of Excellence in Cell Development, and IIT Network, Research Unit of Molecular Neuroscience, Milan, Italy.
3 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
4 Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5 IFOM (FIRC Institute of Molecular Oncology Foundation) Centre of Cell Oncology and Ultrastructure MicroSCoBiO Research Center, Department of Experimental Medicine, University of Genova, Genova, Italy.
6 Nencki Institute of Experimental Biology, Warsaw, Poland.
7 San Raffaele Research Institute, Department of Molecular Oncology, Milan, Italy.
8 Department of Biomedical Sciences, University of Padua, Padua, Italy.
9 Scientific Institute San Raffaele, Experimental Imaging Center, Milan, Italy.

* To whom correspondence should be addressed. E-mail: ppandolf{at} (P.P.P.); pnp{at} (P.P.)

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