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EnglishThe 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.
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| Data di pubblicazione: | 2010 | |
| Titolo: | PML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release. | |
| Autori: | Giorgi C; Ito K; Lin HK; Santangelo C; Wieckowski MR; Lebiedzinska M; Bononi A; Bonora M; Duszynski J; Bernardi R; Rizzuto R; Tacchetti C; Pinton P; Pandolfi PP | |
| Rivista: | SCIENCE | |
| 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. | |
| Digital Object Identifier (DOI): | 10.1126/science.1189157 | |
| Handle: | http://hdl.handle.net/11392/1405985 | |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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