An essential role of the CAAT/enhancer binding protein-α in the vitamin D-induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1)

Chung S. Song, Ibtissam Echchgadda, Young Kyo Seo, Taesung Oh, Soyoung Kim, Sung A. Kim, Sunghwan Cho, Liheng Shi, Bandana Chatterjee

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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. 1α,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-α-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-α 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-α-deficient cells required the expression of cotransfected C/EBP-α; and 3) C/EBP-β did not substitute for C/EBP-α in this regulation. VDR and C/EBP-β 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-α 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-α and VDR in directing 1,25-(OH)2D3-induced expression of a VDR target gene.

Original languageEnglish (US)
Pages (from-to)795-808
Number of pages14
JournalMolecular Endocrinology
Volume20
Issue number4
DOIs
StatePublished - Apr 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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