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Science 2 February 2007:
Vol. 315. no. 5812, pp. 659 - 663
DOI: 10.1126/science.1135380
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Reports

Protein Kinase C ß and Prolyl Isomerase 1 Regulate Mitochondrial Effects of the Life-Span Determinant p66Shc

Paolo Pinton,1,2* Alessandro Rimessi,1,2* Saverio Marchi,1,2 Francesca Orsini,3,4 Enrica Migliaccio,3,4 Marco Giorgio,3,4 Cristina Contursi,5 Saverio Minucci,5 Fiamma Mantovani,6,7 Mariusz R. Wieckowski,1,2,8 Giannino Del Sal,6,7 Pier Giuseppe Pelicci,3,4,9 Rosario Rizzuto1,2{dagger}

The 66-kilodalton isoform of the growth factor adapter Shc (p66Shc) 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 p66Shc was not known. We demonstrate that protein kinase C ß, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66Shc causes alterations of mitochondrial Ca2+ 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.

1 Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrera, Italy.
2 Emilia Romagna Laboratory for Genomics and Biotechnology (ER-Gentech), University of Ferrara, Ferrera, Italy.
3 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
4 Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology, Milan, Italy.
5 Congenia s.r.l., Milan, Italy.
6 Laboratorio Nazionale, Consorzio Interuniversitario per le Biotecnologie, Area Science Park, Trieste, Italy.
7 Department of Biochimica Biofisica Chimica delle Macromolecole, University of Trieste, Italy.
8 Department of Cellular Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Poland.
9 Department of Medicine and Surgery, University of Milan, Italy.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: r.rizzuto{at}unife.it

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