Protein kinase C inhibitor and irradiation-induced apoptosis: Relevance of the cytochrome c-mediated caspase-9 death pathway

Rocha, S., Soengas, M. S., Lowe, S. W., Glanzmann, C., Fabbro, D., Winterhalter, K., Bodis, S., Pruschy, M. (September 2000) Protein kinase C inhibitor and irradiation-induced apoptosis: Relevance of the cytochrome c-mediated caspase-9 death pathway. Cell Growth & Differentiation, 11 (9). pp. 491-499. ISSN 1044-9523

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URL: http://www.ncbi.nlm.nih.gov/pubmed/11007454

Abstract

Caspases are a family of cysteine proteases that constitute the apoptotic cell death machinery, We report the importance of the cytochrome c-mediated caspase-9 death pathway for radiosensitization by the protein kinase C (PKC) inhibitors staurosporine (STP) and PKC-412. In our genetically defined tumor cells, treatment with low doses of STP or the conventional PKC-specific inhibitor PKC-412 in combination with irradiation (5 Gy) potently reduced viability, enhanced mitochondrial cytochrome c release into the cytosol, and specifically stimulated the initiator caspase-9. Whereas treatment with each agent alone had a minimal effect, combined treatment resulted in enhanced caspase-3 activation. This was prevented by broad-range and specific caspase-9 inhibitors and absent in caspase-9-deficient cells. The tumor suppressor p53 was required for apoptosis induction by combined treatment but was dispensable for dose-dependent STP-induced caspase activation. These results demonstrate the requirement for an intact caspase-9 pathway for apoptosis-based radiosensitization by PKC inhibitors and show that STP induces apoptosis independent of p53.

Item Type: Paper
Uncontrolled Keywords: P53-DEPENDENT APOPTOSIS IONIZING-RADIATION TUMOR-CELLS IN-VIVO ACTIVATION CERAMIDE P53 RELEASE MITOCHONDRIA REQUIREMENT
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease > caspases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > Protein kinase C
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: September 2000
Date Deposited: 30 Jan 2014 16:01
Last Modified: 30 Jan 2014 16:01
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29436

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