The vitamin D receptor represses transcription of the pituitary transcription factor Pit-1 gene without involvement of the retinoid X receptor.
Pituitary transcription factor-1 (Pit-1) plays a key role in cell differentiation during organogenesis of the anterior pituitary, and as a transcriptional activator for the pituitary GH and prolactin genes. However, Pit-1 is also expressed in nonpituitary cell types and tissues. In breast tumors, Pit-1 mRNA and protein levels are increased with respect to normal breast, and in MCF-7 human breast adenocarcinoma cells, Pit-1 increases GH secretion and cell proliferation. We report here that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] administration to MCF-7 cells induces a significant decrease in Pit-1 mRNA and protein levels. By deletion analyses, we mapped a region (located between -147 and -171 bp from the transcription start site of the Pit-1 gene) that is sufficient for the repressive response to 1,25-(OH)2D3. Gel mobility shift and chromatin immunoprecipitation assays confirmed the direct interaction between the vitamin D receptor (VDR) as homodimer (without the retinoid X receptor), and the Pit-1 promoter, supporting the view that Pit-1 is a direct transcriptional target of VDR. Our data also indicate that recruitment of histone deacetylase 1 is involved in this repressive effect. This ligand-dependent Pit-1 gene inhibition by VDR in the absence of the retinoid X receptor seems to indicate a new mechanism of transcriptional repression by 1,25-(OH)2D3.
Seoane
Samuel
S
Department of Physiology, School of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Perez-Fernandez
Roman
R
D000107:Acetylation; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D005260:Female; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism*; D050817:Transcription Factor Pit-1 / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D006657:Histones; D018167:Receptors, Calcitriol; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D050817:Transcription Factor Pit-1; D004247:DNA; D002117:Calcitriol