Role of Coactivators and Corepressors in the Induction of the RARβ Gene in Human Colon Cancer Cells(Pharmacology)

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We previously reported that the retinoic acid (RA) insensitivity of RARβ induction is a general feature of human colon cancer cells (Biochem. Pharinacol., 59: 485-496, 2000). In the present investigation, we analyzed potential transcriptional defects associated with the expression of the RARβ gene in colon cancer cells. Transfection of reporter constructs containing the RARβ gene promoter as well as truncated fragments of the promoter showed a significant induction of reporter activity by HA treatment in HA-sensitive HCT-15 cells, but not in HA-resistant DLD-1 cells. The results suggest that the transcriptional defect of RARβ expression may not be due to the presence of a specific cis-element in the RARβ promoter. Next we examined whether coactivators and corepressors of nuclear receptors were involved in the HA sensitivity of colon cancer cells. Transfection of coactivators such as CREB binding protein (CBP) and p300 up-regulated the HA-responsive element present in the RARβ promoter (βRARE) in DLD-1 cells up to the level in HCT-15, while coexpression of the nuclear receptor corepressor (NCoR) suppressed the βRARE activity in HCT-15 cells. The expression level of CBP protein was consistently higher in HCT-15, while that of NCoR and Sin3A was higher in DLD-1 cells. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) increased both basal and HA-induced βRARE activity in DLD-1, indicating that histone deacetylase is involved in the regulation of HARβ gene expression. Taken together, our results show that differential function of coactivators and corepressors may determine the level of HARD induction that may mediate retinoid action in colon cancer cells.
社団法人日本薬学会の論文
2002-10-01

Role of Coactivators and Corepressors in the Induction of the RARβ Gene in Human Colon Cancer Cells(Pharmacology)

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