Synergistic activation of the prolactin promoter by vitamin D receptor and GHF-1: role of the coactivators, CREB-binding protein and steroid hormone receptor coactivator-1 (SRC-1).
PRL gene expression is dependent on the presence of the pituitary-specific transcription factor GHF-1/Pit-1, which is transcribed in a highly restricted manner in cells of the anterior pituitary. In pituitary GH3 cells, vitamin D increases the levels of PRL transcripts and stimulates the PRL promoter. We have analyzed the role ... of GHF-1 and of the vitamin D receptor (VDR) to confer vitamin D responsiveness to the PRL promoter. For this purpose we have used nonpituitary HeLa cells, which do not express GHF-1. We found that VDR activates the PRL promoter both in a ligand-dependent and -independent manner through a sequence located between positions -45/-27 in the proximal 5'-flanking region. This sequence also confers VDR and vitamin D responsiveness to a heterologous promoter. In the context of the PRL gene, VDR requires the presence of GHF-1 to activate the promoter. Truncation of the last 12 C-terminal amino acids of VDR, which contain the ligand-dependent activation function (AF2), abolishes regulation by vitamin D, suggesting that binding of coactivators to this region mediates ligand-dependent stimulation of the PRL promoter by the receptor. Indeed, expression of the coactivators, steroid hormone receptor coactivator-1 (SRC-1) and CREB-binding protein (CBP), significantly enhances the stimulatory effect of vitamin D mediated by the wild-type VDR but not by the AF2 mutant receptor. Furthermore, CBP also increases the activation of the PRL promoter by GHF-1 and the ligand-independent activation by both wild-type and mutant VDR.
Mesh Terms:
Animals, Base Sequence, CREB-Binding Protein, DNA-Binding Proteins, Dimerization, Furylfuramide, Hela Cells, Histone Acetyltransferases, Humans, Molecular Sequence Data, Mutation, Nuclear Proteins, Nuclear Receptor Coactivator 1, Pituitary Neoplasms, Prolactin, Promoter Regions, Genetic, Rats, Receptors, Calcitriol, Receptors, Retinoic Acid, Response Elements, Retinoid X Receptors, Trans-Activators, Transcription Factor Pit-1, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Vitamin D
Animals, Base Sequence, CREB-Binding Protein, DNA-Binding Proteins, Dimerization, Furylfuramide, Hela Cells, Histone Acetyltransferases, Humans, Molecular Sequence Data, Mutation, Nuclear Proteins, Nuclear Receptor Coactivator 1, Pituitary Neoplasms, Prolactin, Promoter Regions, Genetic, Rats, Receptors, Calcitriol, Receptors, Retinoic Acid, Response Elements, Retinoid X Receptors, Trans-Activators, Transcription Factor Pit-1, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Vitamin D
Mol. Endocrinol.
Date: Jul. 01, 1999
PubMed ID: 10406465
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