PML regulates apoptosis at endoplasmic reticulum by modulating calcium release
Authors: Jerzy Duszynski
Paolo Pinton
Hui-Kuan Lin
Massimo Bonora
Pier Paolo Pandolfi
Magdalena Lebiedzinska
Carlo Tacchetti
Carlotta Giorgi
Mariusz R Wieckowski
Clara Santangelo
Rosa Bernardi
Rosario Rizzuto
Angela Bononi
Keisuke Ito
Journal: Science (2010)
Discipline: Multidisciplinary
Keywords: PML tumor suppressor; apoptosis; endoplasmic reticulum; mitochondria-associated membranes; calcium ion transport
Affiliations: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Emilia Romagna Laboratory BioPharmaNet, and Laboratory for Technologies of Advanced Therapies (LTTA) University of Ferrara, Ferrara, Italy., Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA., IFOM (FIRC Institute of Molecular Oncology Foundation) Centre of Cell Oncology and Ultrastructure MicroSCoBiO Research Center, Department of Experimental Medicine, University of Genova, Genova, Italy., Nencki Institute of Experimental Biology, Warsaw, Poland., San Raffaele Research Institute, Department of Molecular Oncology, Milan, Italy., Department of Biomedical Sciences, University of Padua, Padua, Italy., Scientific Institute San Raffaele, Experimental Imaging Center, Milan, Italy.

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 (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. 

Retracted: No

PubPeer comments:
 Figure 3D. * Red boxes: In the ETO treatment column, the two panels appear to show an area of overlap, albeit with a different zoom factor.  , 
 https: www.the-scientist.com news-opinion italian-institute-revokes-appointment-of-cancer-researcher-67709 , 
 Erratum for the Report u201cPML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Releaseu201d by C. Giorgi, K. Ito, H.-K. Lin, C. Santangelo, M. R. Wieckowski, M. Lebiedzinska, A. Bononi, M. Bonora, J. Duszynski, R. Bernardi, R. Rizzuto, C. Tacchetti, P. Pinton, P. P. Pandolfi https: science.sciencemag.org content 371 6536 eabi4740  In the Report u201cPML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release,u201d there is a duplicated image shown in the last panel of Fig. 3D; the same field of cells is shown to represent cells treated with etoposide (ETO) in the presence and absence of the erPML chimera. To determine whether the effects of Pml (promyelocytic leukemia gene) on the regulation of calcium-dependent cell death depended on its localization to the endoplasmic reticulum (ER), the authors generated a chimeric protein targeted to the outer surface of the ER (erPML). The introduction of erPML in Pmlu2212 u2212 mouse embryonic fibroblasts (MEFs) restored sensitivity to apoptosis induced by ER stress but did not restore the sensitivity to ETO (fig. S7A). Figure 3D was intended to show representative microscopic fields of Pmlu2212 u2212 MEFs and Pmlu2212 u2212 expressing erPML before and after treatment with different apoptotic stimuli. However, these images were not used for the statistical analysis, which analyzed flow cytometry data reported in fig. S7A. The corrected Fig. 3D (below) shows images from a newer experiment that confirmed the original results.   The error in Fig. 3D does not undermine the work s conclusion. The authors have repeated the experiments and obtained identical results. , 
 I thank the authors and journal staff for correcting this error. ,