Report

PML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release

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Science  28 Oct 2010:
1189157
DOI: 10.1126/science.1189157

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 in the endoplasmic reticulum (ER) and in the mitochondria-associated membranes (MAM), signaling domains involved in ER-to-mitochondria 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.