Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs)

Molecular and Cellular Endocrinology
Liqiang TouJ M Alexander

Abstract

Cbfa1, a transcription factor critical for bone formation, plays a key role in osteoblast recruitment and differentiation. We have cloned and characterized a 3.0 KB 5'-flanking region of the human cbfa1 gene isolated from a P1 human genomic library. DNA sequencing revealed several known canonical nuclear transcription factor binding sites, including two AP1 and six OSE2 binding sites in the proximal promoter region. Although no estrogen (E2)-response element (ERE) binding sites were identified, E2 has been shown to regulate gene activity via AP1 promoter sites. We examined the effect of selective estrogen receptor modulators (SERMs) on human cbfa1 gene promoter activity using cell-based luciferase reporter transcriptional assays. Three characterized SERMs, tamoxifen, raloxifene, and ICI 178,180, all upregulated cbfa1-luciferase (cbfa1Luc) gene activity 5- to 10-fold in a dose-dependent manner. This effect was mediated by both ER alpha and ER beta. Mutational analysis demonstrated that the minimal promoter region for basal of SERM-activated transcription was mapped to adjacent AP1-like and OSE2 binding sites within -93 and +7 of the transcription start condon. Further, electrophoretic mobility shift assays (EMSAs) demonstrate th...Continue Reading

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Citations

Jul 6, 2005·Osteoporosis International : a Journal Established As Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA·Mei-Ling HoChin Hsu
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