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B. Eickhoff, L. Germeroth, C. Stahl, G. Köhler, S. Rüller, M. Schlaak, J. van der Bosch

Trichostatin A-Mediated Regulation of Gene Expression and Protein Kinase Activities: Reprogramming Tumor Cells for Ribotoxic Stress-Induced Apoptosis

Recently we described a new signal transduction-based tumor therapeutic strategy involving first sensitization of tumor cells by trichostatin A (TSA), an inhibitor of histone deacetylation, and thereafter efficient apoptotic triggering by ribotoxic agents, which activate stress-activated protein kinases. In the present work we investigate the molecular basis of the sensitization step in this therapeutic model system and describe TSA-induced changes in mRNA and protein expression of several candidate genes identified previously by complex hybridization. Furthermore, activities of 15 different protein kinases were followed after TSA application, using a new filter-based technique (PhosphoSpots^®-Assay). The obtained data suggest that TSA induces pro-apoptotic genes like ID1, ID2, ID3, and down-regulates anti-apoptotic genes like Hsp27 and Bcl-xL, thereby shifting the cellular equilibrium from life to death. Furthermore, activities of calcium/calmodulin-dependent kinase II and protein kinase C, which have been assigned pro-apoptotic function in other systems, are induced.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 381, 11/2000
Pages: 1127 - 1132

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