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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 and Pandolfi, PP (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247-51


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 (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 (IP(3)R), protein kinase Akt, and protein phosphatase 2a (PP2a). Pml was essential for Akt- and PP2a-dependent modulation of IP(3)R phosphorylation and in turn for IP(3)R-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.


PubMed PMC3017677 Online version:10.1126/science.1189157


Adenosine Triphosphate/metabolism; Animals; Apoptosis; Calcium/metabolism; Calcium Signaling; Cell Line; Cell Nucleus/metabolism; Cells, Cultured; Cytosol/metabolism; Endoplasmic Reticulum/metabolism; Homeostasis; Humans; Inositol 1,4,5-Trisphosphate/metabolism; Inositol 1,4,5-Trisphosphate Receptors/metabolism; Intracellular Membranes/metabolism; Mice; Mitochondria/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Phosphorylation; Protein Phosphatase 2/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Recombinant Fusion Proteins/metabolism; Stress, Physiological; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism