title: The coupling of epidermal growth factor receptor down regulation by 1alpha,25-dihydroxyvitamin D3 to the hormone-induced cell cycle arrest at the G1-S checkpoint in ovarian cancer cells.
abstract: 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.
authors: Department of Pathology and Cell Biology, USF College of Medicine, Tampa, FL 33612-4799, United States.
authors: Zheng
authors: Z
authors: Shen
authors: Xiaohui
authors: X
authors: Zhang
authors: Jinfu
authors: J
authors: Tang
authors: Ravi
authors: R
authors: Kasiappan
authors: Umesh
authors: U
authors: Jinwal
authors: Pengfei
authors: P
authors: Li
authors: Shan
authors: S
authors: Hann
authors: Santo V
authors: SV
authors: Nicosia
authors: Jie
authors: J
authors: Wu
authors: Xiaohong
authors: X
authors: Zhang
authors: Wenlong
authors: W
authors: Bai
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D007438:Introns; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000503:physiopathology*; D015398:Signal Transduction; D030181:Vitamin D Response Element
chemical_list: D016213:Cyclins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004815:Epidermal Growth Factor; D049409:Luciferases, Firefly; D066246:ErbB Receptors; D002117:Calcitriol