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Transcriptional Regulation of Mitotic Genes by Camptothecin-induced DNA Damage

Microarray Analysis of Dose- and Time-dependent Effects

Laboratory of Molecular Pharmacology, Division of Basic Sciences [Y. Z., F. G. G., W. C. R., L. H. S., U. S., K. W. K., Y. P., J. N. W.], Microarray Facility, Advanced Technology Center, Division of Clinical Sciences [L. D. M.], and Office of the Director, Division of Clinical Sciences [E. T. L.], National Cancer Institute, NIH, Bethesda, Maryland 20892

cDNA microarray technology can be used to establish associations betweencharacteristic gene expression patterns and molecular responses to drug therapy. In this study, we used cDNA microarrays of 1694 cancer-related genes to monitor the gene expression consequences of the treatment of HCT116 colon cancer cells with the topoisomerase I inhibitor camptothecin (CPT). To obtain a more homogeneous cellular response, we synchronized the cells in S-phase using aphidicolin (APH) before CPT treatment. Brief incubation with 20 and 1000 nM CPT caused reversible and irreversible G₂ arrest, respectively, and the patterns of gene expression change (with reference to untreated controls) were strikingly different at the two concentrations. Thirty-three genes, mainly divided into three groups, showed characteristic changes in the first 20 h as a consequence of treatment. Northern blots performed for five of these genes (each under eight experimental conditions) were quite consistent with the microarray results (average correlation coefficient, 0.86). Several p53-activated stress response genes were up-regulated after treatment with 1000 nM CPT or prolonged exposure to APH, but it seemed that the up-regulation did not directly cause cell cycle arrest because the up-regulation induced by prolonged treatment with APH did not prevent cell cycle progression after removal of APH. In contrast, cell cycle-dependent up-regulation of a group of mitosis-related genes was delayed or blocked after CPT treatments. The interrupted up-regulation of this group of genes was directly associated with G₂ arrest. In addition, we observed down-regulation of gene expression in cells that were recovering from cell cycle delay. The observations reported here suggest a fundamental difference at the gene expression level between the molecular mechanism of reversible G₂ delay that follows mild DNA damage and the mechanism of permanent G₂ arrest that follows more extensive DNA damage.

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