期刊
CANCER RESEARCH
卷 65, 期 15, 页码 6557-6567出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-0486
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资金
- NCI NIH HHS [R01CA18119, R01CA70896, R01CA86072, R01CA86071, R01CA82599, R01CA80000, R01CA75503] Funding Source: Medline
- NIA NIH HHS [R03AG20337] Funding Source: Medline
- NIEHS NIH HHS [R01ES109169] Funding Source: Medline
The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor alpha (ER alpha)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERa binding. Cyclin D1 and BRCA1 were both capable of binding ER alpha in a common region of the ER alpha hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ER alpha and for rescue of BRCA1-mediated ER alpha transcriptional repression. In chromatin immunoprecipitation assays, 17 beta-estradiol (E-2) enhanced ER alpha and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ER alpha recruitment to an ERE. E-2 reduced BRCA1 recruitment and BRCA1 expression inhibited E-2-induced ER alpha recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ER alpha recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-inediated ER alpha repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.
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