PML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release

被引：338

作者：

Giorgi, Carlotta ^{[1
,2
,3
,4
,5
,6
,7
]}

Ito, Keisuke ^{[5
,6
,7
]}

Lin, Hui-Kuan ^{[7
]}

Santangelo, Clara ^{[8
,9
]}

Wieckowski, Mariusz R. ^{[10
]}

Lebiedzinska, Magdalena ^{[10
]}

Bononi, Angela ^{[1
,2
]}

Bonora, Massimo ^{[1
,2
]}

Duszynski, Jerzy ^{[10
]}

Bernardi, Rosa ^{[5
,6
,7
,11
]}

Rizzuto, Rosario ^{[12
]}

Tacchetti, Carlo ^{[8
,9
,13
]}

Pinton, Paolo ^{[1
,2
,5
,6
,7
]}

Pandolfi, Pier Paolo ^{[5
,6
,7
]}

机构：

[1] Univ Ferrara, Emilia Romagna Lab BioPharmaNet, Dept Expt & Diagnost Med, Sect Gen Pathol,ICSI, I-44100 Ferrara, Italy

[2] Univ Ferrara, Lab Technol Adv Therapies, I-44100 Ferrara, Italy

[3] Univ Vita Salute San Raffaele, Ctr Excellence Cell Dev, Milan, Italy

[4] IIT Network, Res Unit Mol Neurosci, Milan, Italy

[5] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,Dept Med, Beth Israel Deaconess Canc Ctr,Canc Genet Program, Boston, MA 02215 USA

[6] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,Dept Pathol, Beth Israel Deaconess Canc Ctr,Canc Genet Program, Boston, MA 02215 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Pathol, Canc Biol & Genet Program, New York, NY 10065 USA

[8] Univ Genoa, Ctr Cell Oncol, IFOM FIRC Inst Mol Oncol Fdn, Genoa, Italy

[9] Univ Genoa, Dept Expt Med, Ultrastruct MicroSCoBiO Res Ctr, Genoa, Italy

[10] M Nencki Inst Expt Biol, PL-02093 Warsaw, Poland

[11] San Raffaele Res Inst, Dept Mol Oncol, Milan, Italy

[12] Univ Padua, Dept Biomed Sci, Padua, Italy

[13] Ist Sci San Raffaele, Expt Imaging Ctr, I-20132 Milan, Italy

来源：

SCIENCE | 2010年 / 330卷 / 6008期

关键词：

CA2+ RELEASE; MITOCHONDRIA; BCL-2; CELLS;

D O I：

10.1126/science.1189157

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1247 / 1251

页数：5

共 21 条

[1] Regulation of apoptosis by PML and the PML-NBs [J].