Protein Kinase C ß and Prolyl Isomerase 1 Regulate Mitochondrial Effects of the Life-Span Determinant p66 Shc

American Association for the Advancement of Science (AAAS) - Tập 315 Số 5812 - Trang 659-663 - 2007
Paolo Pinton1,2,3,4,5, Alessandro Rimessi1,2,3,4,5, Saverio Marchi1,2,3,4,5, Francesca Orsini1,2,3,4,5, Enrica Migliaccio1,2,3,4,5, Marco Giorgio1,2,3,4,5, Cristina Contursi1,2,3,4,5, Saverio Minucci1,2,3,4,5, Fiamma Mantovani1,2,3,4,5, Mariusz R. Więckowski1,6,3,4,5, Giannino Del Sal1,2,3,4,5, Pier Giuseppe Pelicci1,2,3,4,5, Rosario Rizzuto1,2,3,4,5
1Congenia s.r.l., Milan, Italy.
2Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
3Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrera, Italy.
4Emilia Romagna Laboratory for Genomics and Biotechnology (ER-Gentech), University of Ferrara, Ferrera, Italy.
5Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology, Milan, Italy.
6Department of Cellular Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Poland.

Tóm tắt

The 66-kilodalton isoform of the growth factor adapter Shc (p66 Shc ) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66 Shc was not known. We demonstrate that protein kinase C β, activated by oxidative conditions in the cell, induces phosphorylation of p66 Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66 Shc causes alterations of mitochondrial Ca 2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.

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Tài liệu tham khảo

10.1038/ng0596-25

10.1038/46311

10.1074/jbc.M511626200

10.1074/jbc.M401844200

10.1016/j.cell.2005.05.011

10.1111/j.1469-7793.2000.00037.x

10.1242/jcs.114.12.2213

10.1093/emboj/18.22.6349

10.1054/ceca.2000.0170

10.1038/11396

10.1042/bj3320281

10.1083/jcb.200311061

10.1016/S0891-5849(00)00221-5

Materials and Methods are available as supporting material on Science Online.

10.1126/science.280.5370.1763

10.1093/emboj/20.11.2690

10.1016/S0968-0004(00)01745-X

10.1023/A:1007321227010

10.1016/S0962-8924(02)02253-5

10.1038/ncb0505-435

10.1038/nature01120

We thank C. Baldini for carrying out some experiments G. A. Rutter for aequorin adenoviruses and T. Pozzan for helpful discussion. This work was supported by grants from the Italian University Ministry (MUR) Telethon Italy (grants GGP05284 and GTF02013) NIH (grant: A mitochondrial longevity pathway: p66 shc mechanisms) NeuroNE the Italian Association for Cancer Research (AIRC) the Italian Space Agency (ASI) European Union (fondi strutturali Obiettivo 2) and the Industrial Research program (PRRIITT) of the Emilia Romagna region.

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American Association for the Advancement of Science (AAAS)

Tập 315 Số 5812

659-663

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