TY - JOUR
T1 - PML regulates apoptosis at endoplasmic reticulum by modulating calcium release
AU - Giorgi, Carlotta
AU - Ito, Keisuke
AU - Lin, Hui Kuan
AU - Santangelo, Clara
AU - Wieckowski, Mariusz R.
AU - Lebiedzinska, Magdalena
AU - Bononi, Angela
AU - Bonora, Massimo
AU - Duszynski, Jerzy
AU - Bernardi, Rosa
AU - Rizzuto, Rosario
AU - Tacchetti, Carlo
AU - Pinton, Paolo
AU - Pandolfi, Pier Paolo
PY - 2010/11/26
Y1 - 2010/11/26
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1189157
DO - 10.1126/science.1189157
M3 - Article
C2 - 21030605
AN - SCOPUS:78649425814
SN - 0036-8075
VL - 330
SP - 1247
EP - 1251
JO - Science
JF - Science
IS - 6008
ER -