PML regulates apoptosis at endoplasmic reticulum by modulating calcium release

Carlotta Giorgi, Keisuke Ito, Hui Kuan Lin, Clara Santangelo, Mariusz R. Wieckowski, Magdalena Lebiedzinska, Angela Bononi, Massimo Bonora, Jerzy Duszynski, Rosa Bernardi, Rosario Rizzuto, Carlo Tacchetti, Paolo Pinton, Pier Paolo Pandolfi

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258 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1247-1251
Number of pages5
JournalScience
Volume330
Issue number6008
DOIs
StatePublished - Nov 26 2010
Externally publishedYes

ASJC Scopus subject areas

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    Giorgi, C., Ito, K., Lin, H. K., Santangelo, C., Wieckowski, M. R., Lebiedzinska, M., Bononi, A., Bonora, M., Duszynski, J., Bernardi, R., Rizzuto, R., Tacchetti, C., Pinton, P., & Pandolfi, P. P. (2010). PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science, 330(6008), 1247-1251. https://doi.org/10.1126/science.1189157