pp60cSrc Is a Caspase-3 Substrate and Is Essential for the Transformed Phenotype of A431 Cells |
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| Institution: | 1. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts;2. Duke University School of Medicine, Durham, North Carolina;1. Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA;2. Department of Mechanical & Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA;3. Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA;4. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA;1. Department of General Surgery, The Third Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China;2. Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada;3. Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China;4. Bioelectromagnetics Laboratory, Department of Public Health, Zhejiang University School of Medicine, China;1. Systematic Review Team, DRG Abacus, 6 Talisman Business Centre, Talisman Road, Bicester OX26 6HR, UK;2. Department of Health Sciences, University of Leicester, Centre for Medicine, University Road, Leicester LE1 7RH, UK;1. Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas;2. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas;3. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas |
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| Abstract: | The protein tyrosine kinase c-Src is a major signal transduction element in many growth factor receptor signals for proliferation and transformation. We showed recently that c-Src is a mediator of antiapoptotic signals through regulation of the antiapoptotic gene Bcl-XL. A431 cells overexpress the EGF receptor (EGFR) and possess high Src activity. In A431 cells, Src is activated by the EGFR, and inhibition of the EGF receptor results in c-Src inhibition. In this study we show that (i) inhibition of the EGFR kinase or Src kinase by specific inhibitors results in growth inhibition and inhibition of colony formation in soft agar. The relative efficacies of the EGFR kinase inhibitor and of the Src kinase inhibitor are similar suggesting the major role src plays in the oncogenic signaling of EGFR in A431 cells. (ii) The Src kinase inhibitor PP1 sensitizes A431 cells to CDDP-induced apoptosis. (iii) CDDP induces caspase-3-dependent cleavage of the c-Src C-terminal portion and a concomitant reduction in Bcl-XL levels. We conclude that c-Src is an important antiapoptotic signaling molecule downstream of the EGF receptor that contributes to the transformed phenotype of A431 cells. |
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