PML regulates apoptosis at endoplasmic reticulum by modulating calcium release

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-associa...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Science (American Association for the Advancement of Science) Jg. 330; H. 6008; S. 1247
Hauptverfasser: Giorgi, Carlotta, Ito, Keisuke, Lin, Hui-Kuan, Santangelo, Clara, Wieckowski, Mariusz R, Lebiedzinska, Magdalena, Bononi, Angela, Bonora, Massimo, Duszynski, Jerzy, Bernardi, Rosa, Rizzuto, Rosario, Tacchetti, Carlo, Pinton, Paolo, Pandolfi, Pier Paolo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 26.11.2010
Schlagworte:
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
Promyelocytic Leukemia Protein
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
ISSN:1095-9203, 1095-9203
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1095-9203
1095-9203
DOI:10.1126/science.1189157