AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Cell Biology
Medical Subject Headings
Animals; DNA; Humans; Inhibitor of Apoptosis Proteins; Osteocalcin; Promoter Regions (Genetics); Rats; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoid X Receptors; *Signal Transduction; Trans-Activation (Genetics); Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Viral Proteins
Life Sciences | Medicine and Health Sciences
Responsiveness of genes to steroid hormones is a complex process involving synergistic and/or antagonistic interactions between specific receptors and other nonreceptor transcription factors. Thus, DNA recognition elements for steroid hormone receptors are often located among binding sites for other trans-acting factors. The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, stimulates transcription of the tissue-specific osteocalcin (OC) gene in osteoblastic cells. The rat OC vitamin D response element contains an internal acitvating protein-1 (AP-1) site. Here, we report for the first time that this AP-1 site is critical for the transcriptional enhancement of rat osteocalcin gene expression mediated by vitamin D. Precise mutations were introduced either in the steroid half-elements or in the internal AP-1 sequences. One mutation within the internal AP-1 site retained vitamin D receptor/retinoid X receptor binding equivalent to that of the wild-type sequence, but resulted in complete loss of vitamin D inducibility of the OC promoter. These results suggest a functional interaction between the hormone receptor and nuclear oncoproteins at the rat OC vitamin D response element. This cooperation of activities may have important consequences in physiological regulation of osteocalcin transcription during osteoblast differentiation and bone tissue development in vivo.
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Citation: Endocrinology. 1999 Jan;140(1):63-70.