Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 330 (6008): 1247-1251

Copyright © 2010 by the American Association for the Advancement of Science

PML Regulates Apoptosis at Endoplasmic Reticulum by Modulating Calcium Release

Carlotta Giorgi,1,2,3,4 Keisuke Ito,3,4 Hui-Kuan Lin,4 Clara Santangelo,5 Mariusz R. Wieckowski,6 Magdalena Lebiedzinska,6 Angela Bononi,1 Massimo Bonora,1 Jerzy Duszynski,6 Rosa Bernardi,3,4,7 Rosario Rizzuto,8 Carlo Tacchetti,5,9 Paolo Pinton,1,3,4,* Pier Paolo Pandolfi3,4,*

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.

1 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.
2 Vita-Salute San Raffaele University, Center of Excellence in Cell Development, and IIT Network, Research Unit of Molecular Neuroscience, Milan, Italy.
3 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.
4 Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5 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.
6 Nencki Institute of Experimental Biology, Warsaw, Poland.
7 San Raffaele Research Institute, Department of Molecular Oncology, Milan, Italy.
8 Department of Biomedical Sciences, University of Padua, Padua, Italy.
9 Scientific Institute San Raffaele, Experimental Imaging Center, Milan, Italy.

* To whom correspondence should be addressed. E-mail: ppandolf{at}bidmc.harvard.edu (P.P.P.); pnp{at}unife.it (P.P.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodelling of the isoform composition of IP3Rs and ER luminal Ca2+ levels in colorectal cancer cell lines.
C. Pierro, S. J. Cook, T. C. F. Foets, M. D. Bootman, and H. L. Roderick (2014)
J. Cell Sci. 127, 1607-1619
   Abstract »    Full Text »    PDF »
Where is mTOR and what is it doing there?.
C. Betz and M. N. Hall (2013)
J. Cell Biol. 203, 563-574
   Abstract »    Full Text »    PDF »
The Disturbances of Endoplasmic Reticulum Calcium Homeostasis Caused by Increased Intracellular Reactive Oxygen Species Contributes to Fragmentation in Aged Porcine Oocytes.
D.-W. Tang, Y. Fang, Z.-X. Liu, Y. Wu, X.-L. Wang, S. Zhao, G.-C. Han, and S.-M. Zeng (2013)
Biol Reprod 89, 124
   Abstract »    Full Text »    PDF »
Depressing Mitochondria-Reticulum Interactions Protects Cardiomyocytes From Lethal Hypoxia-Reoxygenation Injury.
M. Paillard, E. Tubbs, P.-A. Thiebaut, L. Gomez, J. Fauconnier, C. Crola Da Silva, G. Teixeira, N. Mewton, E. Belaidi, A. Durand, et al. (2013)
Circulation 128, 1555-1565
   Abstract »    Full Text »    PDF »
Mfn2 modulates the UPR and mitochondrial function via repression of PERK.
J. P. Munoz, S. Ivanova, J. Sanchez-Wandelmer, P. Martinez-Cristobal, E. Noguera, A. Sancho, A. Diaz-Ramos, M. I. Hernandez-Alvarez, D. Sebastian, C. Mauvezin, et al. (2013)
EMBO J. 32, 2348-2361
   Abstract »    Full Text »    PDF »
mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology.
C. Betz, D. Stracka, C. Prescianotto-Baschong, M. Frieden, N. Demaurex, and M. N. Hall (2013)
PNAS 110, 12526-12534
   Abstract »    Full Text »    PDF »
Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle - pivotal roles in Ca2+ and reactive oxygen species signaling.
V. Eisner, G. Csordas, and G. Hajnoczky (2013)
J. Cell Sci. 126, 2965-2978
   Abstract »    Full Text »    PDF »
Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen.
Y.-L. Chung (2013)
FASEB J 27, 2316-2327
   Abstract »    Full Text »    PDF »
Selective inhibition of the NLRP3 inflammasome by targeting to promyelocytic leukemia protein in mouse and human.
Y.-H. Lo, Y.-W. Huang, Y.-H. Wu, C.-S. Tsai, Y.-C. Lin, S.-T. Mo, W.-C. Kuo, Y.-T. Chuang, S.-T. Jiang, H.-M. Shih, et al. (2013)
Blood 121, 3185-3194
   Abstract »    Full Text »    PDF »
Ultrastructural Pathology and Interorganelle Cross Talk in Hepatotoxicity.
N. F. Cheville (2013)
Toxicol Pathol 41, 210-226
   Abstract »    Full Text »    PDF »
The Filamentous Growth MAPK Pathway Responds to Glucose Starvation Through the Mig1/2 Transcriptional Repressors in Saccharomyces cerevisiae.
S. Karunanithi and P. J. Cullen (2012)
Genetics 192, 869-887
   Abstract »    Full Text »    PDF »
The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling.
E. Lang, A. Grudic, S. Pankiv, O. Bruserud, A. Simonsen, R. Bjerkvig, M. Bjoras, and S. O. Boe (2012)
Blood 120, 847-857
   Abstract »    Full Text »    PDF »
Intermediate progenitors are increased by lengthening of the cell cycle through calcium signaling and p53 expression in human neural progenitors.
E. Garcia-Garcia, M. J. Pino-Barrio, L. Lopez-Medina, and A. Martinez-Serrano (2012)
Mol. Biol. Cell 23, 1167-1180
   Abstract »    Full Text »    PDF »
The Hepatitis B Virus X Protein Elevates Cytosolic Calcium Signals by Modulating Mitochondrial Calcium Uptake.
B. Yang and M. J. Bouchard (2012)
J. Virol. 86, 313-327
   Abstract »    Full Text »    PDF »
Mitogen-activated Protein Kinase Extracellular Signal-regulated Kinase 2 Phosphorylates and Promotes Pin1 Protein-dependent Promyelocytic Leukemia Protein Turnover.
J. H. Lim, Y. Liu, E. Reineke, and H.-Y. Kao (2011)
J. Biol. Chem. 286, 44403-44411
   Abstract »    Full Text »    PDF »
Ion channels and transporters in cancer. 4. Remodeling of Ca2+ signaling in tumorigenesis: role of Ca2+ transport.
J. M. Lee, F. M. Davis, S. J. Roberts-Thomson, and G. R. Monteith (2011)
Am J Physiol Cell Physiol 301, C969-C976
   Abstract »    Full Text »    PDF »
PMLRAR{alpha} binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo.
R.-H. Tao, Z. Berkova, J. F. Wise, A.-H. Rezaeian, U. Daniluk, X. Ao, D. H. Hawke, J. E. Karp, H.-K. Lin, J. J. Molldrem, et al. (2011)
Blood 118, 3107-3118
   Abstract »    Full Text »    PDF »
The Alphaherpesvirus Serine/Threonine Kinase Us3 Disrupts Promyelocytic Leukemia Protein Nuclear Bodies.
M. Jung, R. L. Finnen, C. E. Neron, and B. W. Banfield (2011)
J. Virol. 85, 5301-5311
   Abstract »    Full Text »    PDF »
Puzzled by PML.
B. Culjkovic-Kraljacic and K. L. B. Borden (2010)
Science 330, 1183-1184
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882