Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc

Paolo Pinton; Alessandro Rimessi; Saverio Marchi; Francesca Orsini; Enrica Migliaccio; Marco Giorgio; Cristina Contursi; Saverio Minucci; Fiamma Mantovani; Mariusz R Wieckowski; Giannino Del Sal; Pier Giuseppe Pelicci; Rosario Rizzuto

doi:10.1126/science.1135380

Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc

Science. 2007 Feb 2;315(5812):659-63. doi: 10.1126/science.1135380.

Authors

Paolo Pinton¹, Alessandro Rimessi, Saverio Marchi, Francesca Orsini, Enrica Migliaccio, Marco Giorgio, Cristina Contursi, Saverio Minucci, Fiamma Mantovani, Mariusz R Wieckowski, Giannino Del Sal, Pier Giuseppe Pelicci, Rosario Rizzuto

Affiliation

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.

PMID: 17272725
DOI: 10.1126/science.1135380

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Adenosine Triphosphate / metabolism
Adenosine Triphosphate / pharmacology
Animals
Apoptosis*
Calcium / metabolism
Calcium Signaling
Cell Survival
Cells, Cultured
Cellular Senescence*
Cyclosporine / pharmacology
Hydrogen Peroxide / metabolism
Hydrogen Peroxide / pharmacology
Mice
Mitochondria / metabolism*
Mitochondria / ultrastructure
Mutation
NIMA-Interacting Peptidylprolyl Isomerase
Oxidative Stress
Peptidylprolyl Isomerase / metabolism*
Permeability
Phosphorylation
Protein Kinase C / antagonists & inhibitors
Protein Kinase C / genetics
Protein Kinase C / metabolism*
Protein Kinase C beta
Reactive Oxygen Species / metabolism
Recombinant Fusion Proteins / metabolism
Shc Signaling Adaptor Proteins
Signal Transduction*
Src Homology 2 Domain-Containing, Transforming Protein 1

Substances

Adaptor Proteins, Signal Transducing
NIMA-Interacting Peptidylprolyl Isomerase
Reactive Oxygen Species
Recombinant Fusion Proteins
Shc Signaling Adaptor Proteins
Shc1 protein, mouse
Src Homology 2 Domain-Containing, Transforming Protein 1
Cyclosporine
Adenosine Triphosphate
Hydrogen Peroxide
Protein Kinase C
Protein Kinase C beta
Peptidylprolyl Isomerase
Pin1 protein, mouse
Calcium

Grants and funding

GGP05284/TI_/Telethon/Italy