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Mechanism for Inactivation of the KIP Family Cyclin-dependent Kinase Inhibitor Genes in Gastric Cancer Cells¹

Department of Biochemistry, College of Medicine [J-Y. S., H-S. K., J-B. P., J-Y. L.], Department of Genetic Engineering [J. P.], and Institute of Environment & Life Science [J. P., J-B. P., J-Y. L.], Hallym University, Chunchon, Kangwon-do 200-702, South Korea

The mechanism for inactivation of the KIP family cyclin-dependent kinase inhibitor (CDKI) genes, the p21, p27, and p57 genes, in gastric cancer cells was tested by treating the cells with either the DNA demethylation agent, 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor, n-butyric acid or trichostatin A. RNA expression of the gene was determined by reverse transcription PCR. The p21 gene was activated only by histone deacetylase inhibitor. The p57 gene was activated by histone deacetylase inhibitors in all of the gastric cancer cell lines and by 5-aza-2'-deoxycytidine in five of eight gastric cell lines. However, the p27 gene was not inactivated in gastric cancer cell lines. The methylation status of the promoter of the p21 and p57 genes was also tested by digestion with the methylation-sensitive restriction enzymes and a subsequent PCR. The promoter of the p21 gene has no methylation. The promoter of the p57 gene is, however, methylated in five of eight gastric cancer cell lines as expected from the result of the treatment with 5-aza-2'-deoxycytidine. Formation of the inactive chromatin through histone deacetylation seems to be the general mechanism for inactivation of both the p21 and the p57 genes in gastric cancer cells. Hypermethylation of promoter region seems to be an alternative pathway for inactivation of the p57 gene.

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