HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7 alpha-hydroxylase gene (CYP7A1)

HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7 alpha-hydroxylase gene (CYP7A1)

Stroup D; Chiang J Y L

Journal of Lipid Research

2000

2000-01

The gene for cholesterol 7 alpha-hydroxylase (CYP7A1) contains a sequence at nt -149 to -118 that was found to play a large role in determining the overall transcriptional activity and regulation of the promoter. Hepatocyte nuclear factor 4 (HNF4) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) synergistically activate transcription of the CYP7A1 promoter, Transactivation of CYP7A1 by HNF4 in the human hepatoma cell line, HepG2, was enhanced by cotransfection with COUP-TFII or the basal transcription element binding protein (BTEB), HNF4 prepared from rat liver nuclear extracts bound to oligomers homologous to the nt -146 to -134 sequences in electrophoretic mobility shift assays (EMSA), which corresponded to a conserved region containing a direct repeat of hormone response elements spaced by one nucleotide (DR1), The sequences surrounding this DR1 were found to be essential for the HNF4 transactivation. In vitro-translated COUP-TFII was found to bind the adjacent sequences from nt -139 to -128 (DRO), but COUP-TFII interacted with this region at a much lower affinity than to the COUP-TFII-site at nt -72 to -57 (DR4), Mutations at nt -139 to -128 or nt -72 to -57 reduced the COUP-TFII and HNF4 synergy; however, these COUP-TFII-binding sequences were not absolutely required for the cooperative effect of HNF4 and COUP-TFII on transactivation. These results indicated that the observed transactivation was the result of protein/protein interactions facilitated by the juxtaposition of the binding elements.

bile-acid synthesis; bile acids; Biochemistry & Molecular Biology; chicken ovalbumin; cholesterol metabolism; dna-binding; hepatocyte nuclear factor 4; hepatocyte nuclear factor 4; hormone-receptor superfamily; messenger-rna; orphan receptors; promoter; receptors; response elements; retinoic acid; thyroid-hormone; transcriptional regulation; upstream promoter transcription factor II

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Journal Article

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