Nucleic Acids Research, 1994, Vol. 22, No. 22 4689-4696
© 1994
MOLECULAR BIOLOGY |
Transcriptional regulation of the apolipoprotein A-IV gene involves synergism between a proximal orphan receptor response element and a distant enhancer located in the upstream promoter region of the apolipoprotein C-III gene
Institut of Molecular Biology and Biotechnology, Foundation for Research and Technology and University of Crete School PO Box 1527, Herakleion 711 10, Crete, Greece
*To whom correspondence should be addressed
Received July 6, 1994. Revised October 23, 1994. Accepted October 23, 1994.
Apolipoprotein A-IV expression is limited to intestinal and hepatic cells, suggesting a tissue specific transcriptional regulation of its gene. To investigate the mechanism controlling apo A-IV transcription we have analysed its promoter region by in vitro DNA binding and transient transfection experiments. DNase I footprinting analysis of the proximal promoter with rat liver nuclear extracts revealed four protected regions: AlVA ( –32 to –22), AlVB ( –84 to –42), AlVC (–148 to –92) and AIVD ( –274 to –250). Element AIVC which is necessary for maximal promoter activity, binds HNF-4, Arp-1 and Ear-3 with similar affinity in a mutually exclusive manner. HNF-4 transactivated chimeric constructs containing intact AIVC site in the context of either the apo A-IV promoter or the heterologous thymidine kinase minimal promoter, while Arp-1 and Ear-3 repressed this activation. Increasing amounts of HNF-4 alleviated Arp-1 or Ear-3 mediated repression, suggesting that the observed opposing effects is a result of direct competition of these factors for the same recognition site. In transient transfection assays the apo A-IV promoter region (–700 to +10) had a very low activity in cells of hepatic (HepG2) and intestinal (CaCo2) origin. This activity was increased 13 to 18-fold when the upstream elements of the distantly linked apo C-lll gene were fused to the proximal promoter. Results obtained with different 5' and 3' deletion constructs indicated that the cis-acting elements F to J between the nucleotides –500 and –890 of the apo C-lll promoter were absolutely necessary to drive maximal enhancement in HepG2 and CaCo2 cells. The apo C-lll upstream elements enhanced the activity of the minimal Ad ML promoter or the apo A-IV site C mutant less efficiently than the intact apo A-IV or AdML promoter constructs containing single HNF-4 sites. The findings suggest that the enhancer effect is mediated by synergistic interactions between the frans-acting factors which recognize the apo C-lll regulatory elements and HNF-4 which binds to the proximal apo A-IV promoter.
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