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An Essential Role of the CAAT/Enhancer Binding Protein- in the Vitamin D-Induced Expression of the Human Steroid/Bile Acid-Sulfotransferase (SULT2A1)

Department of Molecular Medicine/Institute of Biotechnology (C.S.S., I.E., Y.-K.S., T.O., S.K., S.-A.K., S.C., L.S., B.C.), The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245; and South Texas Veterans Health Care System (S.K., S.C., B.C.), Audie L. Murphy Veterans Affairs Hospital, San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Bandana Chatterjee, Ph.D., Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245. E-mail: chatterjee{at}uthscsa.edu.

The vitamin D receptor (VDR) regulates steroid and drug metabolism by inducing the genes encoding phase I and phase II enzymes. SULT2A1 is a liver- and intestine-expressed sulfo-conjugating enzyme that converts the alcohol-OH of neutral steroids, bile acids, and drugs to water-soluble sulfated metabolites. 1,25-Dihydroxyvitamin D₃ [1,25-(OH)₂D₃] induces SULT2A1 gene transcription after the recruitment of VDR to the vitamin D-responsive chromatin region of SULT2A1. A composite element in human SULT2A1 directs the 1,25-(OH)₂D₃-mediated induction of natural and heterologous promoters. This element combines a VDR/retinoid X receptor--binding site [vitamin D response element (VDRE)], which is an imperfect inverted repeat 2 of AGCTCA, and a CAAT/enhancer binding protein (C/EBP)-binding site located 9 bp downstream to VDRE. The binding sites were identified by EMSA, antibody supershift, and deoxyribonuclease I footprinting. C/EBP- at the composite element plays an essential role in the VDR regulation of SULT2A1, because 1) induction was lost for promoters with inactivating mutations at the VDRE or C/EBP element; 2) SULT2A1 induction by 1,25-(OH)₂D₃ in C/EBP--deficient cells required the expression of cotransfected C/EBP-; and 3) C/EBP-ß did not substitute for C/EBP- in this regulation. VDR and C/EBP- were recruited concurrently to the composite element along with the coactivators p300, steroid receptor coactivator 1 (SRC-1), and SRC-2, but not SRC-3. VDR and C/EBP- associated endogenously as a DNA-dependent, coimmunoprecipitable complex, which was detected at a markedly higher level in 1,25-(OH)₂D₃-treated cells. These results provide the first example of the essential role of the interaction in cis between C/EBP- and VDR in directing 1,25-(OH)₂D₃-induced expression of a VDR target gene.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  RXRα

Coregulators:   p300  |  SRC-1  |  GRIP1  |  AIB1  |  NCOR

Ligands:   Calcitriol

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