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Sambucetti, L C; Fischer, D D; Zabludoff, S; Kwon, P O; Chamberlin, H; Trogani, N; Xu, H; Cohen, D
Journal of biological chemistry/The Journal of biological chemistry, 12/1999, Letnik: 274, Številka: 49Journal Article
Histone acetylation is emerging as a major regulatory mechanism thought to modulate gene expression by altering the accessibility of transcription factors to DNA. In this study, treatment of human tumor cells with the histone deacetylase inhibitor, trapoxin (TPX), resulted in selective changes in genes that control the cell cycle. TPX activated p21 waf1 transcription that led to elevated p21 waf1 protein levels in three human tumor cell lines without altering the protein levels of cdk2, cdk4, or cyclin B. In addition, TPX increased cyclin E transcription without increasing the levels of Rb, E2F, dihydrofolate reductase, or glyceraldehyde-3-phosphate dehydrogenase. The elevated levels of p21 waf1 protein led to decreased Rb phosphorylation and cdk2 activity. These effects resulted in G 1 and G 2 cell cycle arrest in H1299 human lung and MDA-MB-435 breast carcinoma cells and apoptosis in A549 lung carcinoma cells. Chromatin immunoprecipitation assays revealed that TPX increased the level of chromatin acetylation associated with histone H3 in the trapoxin-responsive region of the p21 waf1 promoter. This study demonstrates that inhibition of HDAC by TPX increases acetylation of H3-associated chromatin and alters gene expression with marked selectivity.
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