Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc.
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.
Pinton
Paolo
P
Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrera, Italy.
Rimessi
Alessandro
A
Marchi
Saverio
S
Orsini
Francesca
F
Migliaccio
Enrica
E
Giorgio
Marco
M
Contursi
Cristina
C
Minucci
Saverio
S
Mantovani
Fiamma
F
Wieckowski
Mariusz R
MR
Del Sal
Giannino
G
Pelicci
Pier Giuseppe
PG
Rizzuto
Rosario
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D016572:Cyclosporine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018384:Oxidative Stress; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010539:Permeability; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D002118:Calcium