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 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 (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 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.

PML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release.

GIORGI, Carlotta;BONONI, Angela;BONORA, Massimo;PINTON, Paolo;
2010

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 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 (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 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.
Giorgi, Carlotta; Ito, K; Lin, Hk; Santangelo, C; Wieckowski, Mr; Lebiedzinska, M; Bononi, Angela; Bonora, Massimo; Duszynski, J; Bernardi, R; Rizzuto, R; Tacchetti, C; Pinton, Paolo; Pandolfi, Pp
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1405985
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