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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: Publikationen MPI-CBG 2010-arch     Display Documents



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ID: 546660.0, MPI für molekulare Zellbiologie und Genetik / Publikationen MPI-CBG 2010-arch
PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1alpha.
Authors:Eke, Iris; Koch, Ulrike; Hehlgans, Stephanie; Sandfort, Veit; Stanchi, Fabio; Zips, Daniel; Baumann, Michael; Shevchenko, Anna; Pilarsky, Christian; Haase, Michael; Baretton, Gustavo; Calleja, Véronique; Larijani, Banafshé; Fässler, Reinhard; Cordes, Nils
Date of Publication (YYYY-MM-DD):2010
Title of Journal:The Journal of Clinical Investigation
Volume:120
Issue / Number:7
Start Page:2516
End Page:2527
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Tumor cell resistance to ionizing radiation and chemotherapy is a major obstacle in cancer therapy. One factor contributing to this is integrin-mediated adhesion to ECM. The adapter protein particularly interesting new cysteine-histidine-rich 1 (PINCH1) is recruited to integrin adhesion sites and promotes cell survival, but the mechanisms underlying this effect are not well understood. Here we have shown that PINCH1 is expressed at elevated levels in human tumors of diverse origins relative to normal tissue. Furthermore, PINCH1 promoted cell survival upon treatment with ionizing radiation in vitro and in vivo by perpetuating Akt1 phosphorylation and activity. Mechanistically, PINCH1 was found to directly bind to protein phosphatase 1alpha (PP1alpha) - an Akt1-regulating protein - and inhibit PP1alpha activity, resulting in increased Akt1 phosphorylation and enhanced radioresistance. Thus, our data suggest that targeting signaling molecules such as PINCH1 that function downstream of focal adhesions (the complexes that mediate tumor cell adhesion to ECM) may overcome radio- and chemoresistance, providing new therapeutic approaches for cancer.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:nn
Affiliations:MPI für molekulare Zellbiologie und Genetik
Identifiers:LOCALID:4331
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