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PMID: 7984419 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

Nucleic acids research ·Vol. 22 ·No. 22 ·1994-11-11 ·Pages 4689-96

Ktistaki E, Lacorte JM, Katrakili N, Zannis VI, Talianidis I

Abstract

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: AIVA (-32 to -22), AIVB (-84 to -42), AIVC (-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-III 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-III promoter were absolutely necessary to drive maximal enhancement in HepG2 and CaCo2 cells. The apo C-III upstream elements enhanced the activity of the minimal AdML 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 trans-acting factors which recognize the apo C-III regulatory elements and HNF-4 which binds to the proximal apo A-IV promoter.

MeSH Terms
Animals Apolipoprotein C-III Apolipoproteins A/genetics Apolipoproteins C/genetics Base Sequence COUP Transcription Factor I COUP Transcription Factor II COUP Transcription Factors Cells, Cultured DNA-Binding Proteins/metabolism Enhancer Elements, Genetic/genetics Gene Expression Regulation/physiology Hepatocyte Nuclear Factor 4 Intestines/cytology Liver/chemistry,cytology Molecular Sequence Data Organ Specificity Phosphoproteins Promoter Regions, Genetic/genetics Rats Receptors, Steroid/metabolism Regulatory Sequences, Nucleic Acid/genetics Trans-Activators/physiology Transcription Factors/metabolism Transcription, Genetic
Chemicals
Apolipoprotein C-III Apolipoproteins A Apolipoproteins C COUP Transcription Factor I COUP Transcription Factor II COUP Transcription Factors DNA-Binding Proteins Hepatocyte Nuclear Factor 4 Nr2f1 protein, rat Nr2f2 protein, rat Phosphoproteins Receptors, Steroid Trans-Activators Transcription Factors apolipoprotein A-IV
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ktistaki E
Institute of Molecular Biology and Biotechnology, University of Crete Medical School, Greece.
Lacorte J M
Katrakili N
Zannis V I
Talianidis I
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
0305-1048
DOI
10.1093/nar/22.22.4689
Published
1994-11-11
Pages
4689-96
Language
English
Region
England
NLM ID
0411011
PMCID
PMC308519
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/22.22.4689 PMC Full Text View journal details
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