期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 338, 期 1-2, 页码 58-67出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2011.02.023
关键词
Cell cycle; EGF; EGFR; Ovarian cancer; Vitamin D; Vitamin D receptor
资金
- NIH [CA111334, R01CA077467]
- Florida Department of Health [06BCBG1]
1alpha,25-dihydroxyvitamin D3, 1,25(OH)(2)D-3, regulates gene expression through the vitamin D receptor. The present studies identify the epidermal growth factor receptor, EGFR, as a target gene suppressed by 1,25(OH)(2)D-3 in human ovarian cancer cells. The suppression was detected at both mRNA and protein levels in vitamin D-sensitive human ovarian cancer cells. A novel vitamin D response element was identified in intron 1 of the EGFR genome, a known hotspot for its transcriptional regulation. Chromatin immunoprecipitations and reporter gene analyses showed that the intronic DNA element bound to vitamin D receptor and a co-repressor and was functional in mediating transcriptional suppression of EGFR promoter by 1,25(OH)(2)D-3 under stable transfection conditions. Consistent with the EGFR down regulation, 1,25(OH)(2)D-3 suppressed activation of the external signal regulated kinase by epidermal growth factors. Over expression of an active EGFR in vitamin D sensitive ovarian cancer cells caused resistance to 1,25(OH)(2)D-3-induced growth suppression and diminished the hormonal regulation of cyclin D1, cyclin E, Skp2 and p27, a group of cell cycle regulators that mediate 1,25(OH)(2)D-3-induced cell cycle arrest at G1-S checkpoint. Taken together, our studies demonstrate that 1,25(OH)(2)D-3 suppresses the response of human ovarian cancer cells to mitogenic growth factors and couple the suppression to the cell cycle arrest at G1-S checkpoint by the hormone. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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