Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y Journal Article
| Authors: | Jin, S.; Scotto, K. W. |
| Article Title: | Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y |
| Abstract: | Recent studies have shown that the histone-modifying enzymes histone acetyltransferase (HAT) and histone deacetylase (HDAC) are involved in transcriptional activation and repression, respectively. However, little is known about the endogenous genes that are regulated by these enzymes or how specificity is achieved. In the present report, we demonstrate that HAT and HDAC activities modulate transcription of the P-glycoproteinencoding gene, MDRI. Incubation of human colon carcinoma SW620 cells in 100-ng/ml trichostatin A (TSA), a specific HDAC inhibitor, increased the steady-state level of MDRI mRNA 20-fold. Furthermore, TSA treatment of cells transfected with a wild-type MDR1 promoter/luciferase construct resulted in a 10- to 15- fold induction of promoter activity. Deletion and point mutation analysis determined that an inverted CCAAT box was essential for this activation. Consistent with this observation, overexpression of p300/CREB binding protein-associated factor (P/CAF), a transcriptional coactivator with intrinsic HAT activity, activated the wild-type MDR1 promoter but not a promoter containing a mutation in the CCAAT box; deletion of the P/CAF HAT domain abolished activation. Gel shift and supershift analyses identified NF- Y as the CCAAT-box binding protein in these cells, and cotransfection of a dominant negative NF-Y expression vector decreased the activation of the MDRI promoter by TSA. Moreover, NF-YA and P/CAF were shown to interact in vitro. This is the first report of a natural promoter that is modulated by HAT and HDAC activities in which the transcription factor mediating this regulation has been identified. |
| Keywords: | controlled study; human cell; promoter region; gene deletion; dna-binding proteins; cell cycle proteins; gene overexpression; luciferase; transcription factor; transcription, genetic; cancer cell culture; tumor cells, cultured; enzyme activity; transcription factors; gene expression regulation; transcription regulation; messenger rna; enzyme inhibitors; hydroxamic acids; binding sites; genes, reporter; saccharomyces cerevisiae proteins; point mutation; colon carcinoma; luciferases; histone deacetylases; multidrug resistance; acetyltransferases; p-glycoprotein; histone deacetylase; ccaat-enhancer-binding proteins; trichostatin a; cyclic amp responsive element binding protein; expression vector; glycoprotein p; promoter regions (genetics); histone acetyltransferase; histone acetyltransferases; humans; human; priority journal; article; clenbuterol |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 18 |
| Issue: | 7 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 1998-07-01 |
| Start Page: | 4377 |
| End Page: | 4384 |
| Language: | English |
| PUBMED: | 9632821 |
| PROVIDER: | scopus |
| PMCID: | PMC109021 |
| DOI: | 10.1128/MCB.18.7.4377 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 12 December 2016 -- Source: Scopus |
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