PML regulates apoptosis at endoplasmic reticulum by modulating calcium release Journal Article

   

Authors:	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.
Article Title:	PML regulates apoptosis at endoplasmic reticulum by modulating calcium release
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.
Keywords:	protein kinase b; protein phosphorylation; nonhuman; animals; mice; cells, cultured; apoptosis; stress, physiological; cell line; calcium; enzyme activity; phosphorylation; transcription factors; nuclear proteins; endoplasmic reticulum; recombinant fusion proteins; tumor suppressor proteins; proto-oncogene proteins c-akt; promyelocytic leukemia; molecular analysis; cell fractionation; cell nucleus; adenosine triphosphate; tumor; homeostasis; mitochondrial membrane; mitochondria; mitochondrion; cytosol; particle size; pleiotropy; fibroblast culture; drug; inositol 1,4,5 trisphosphate receptor; phosphoprotein phosphatase 2a; ion; membrane; calcium transport; calcium signaling; inositol 1,4,5-trisphosphate; inositol 1,4,5-trisphosphate receptors; intracellular membranes; protein phosphatase 2
Journal Title:	Science
Volume:	330
Issue:	6008
ISSN:	0036-8075
Publisher:	American Association for the Advancement of Science
Date Published:	2010-11-26
Start Page:	1247
End Page:	1251
Language:	English
DOI:	10.1126/science.1189157
PUBMED:	21030605
PROVIDER:	scopus
PMCID:	PMC3017677
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-78649425814&partnerID=40&md5=2a730be9cdc29e41dfdf573d9dcc4734
Notes:	--- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: SCIEA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/4138