Publication Date:
2007-02-03
Description:
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 beta, 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pinton, Paolo -- Rimessi, Alessandro -- Marchi, Saverio -- Orsini, Francesca -- Migliaccio, Enrica -- Giorgio, Marco -- Contursi, Cristina -- Minucci, Saverio -- Mantovani, Fiamma -- Wieckowski, Mariusz R -- Del Sal, Giannino -- Pelicci, Pier Giuseppe -- Rizzuto, Rosario -- GGP05284/Telethon/Italy -- New York, N.Y. -- Science. 2007 Feb 2;315(5812):659-63.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrera, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17272725" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing/genetics/*metabolism
;
Adenosine Triphosphate/metabolism/pharmacology
;
Animals
;
*Apoptosis
;
Calcium/metabolism
;
Calcium Signaling
;
*Cell Aging
;
Cell Survival
;
Cells, Cultured
;
Cyclosporine/pharmacology
;
Hydrogen Peroxide/metabolism/pharmacology
;
Mice
;
Mitochondria/*metabolism/ultrastructure
;
Mutation
;
Oxidative Stress
;
Peptidylprolyl Isomerase/*metabolism
;
Permeability
;
Phosphorylation
;
Protein Kinase C/antagonists & inhibitors/genetics/*metabolism
;
Protein Kinase C beta
;
Reactive Oxygen Species/metabolism
;
Recombinant Fusion Proteins/metabolism
;
Shc Signaling Adaptor Proteins
;
*Signal Transduction
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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