© 1997 American Heart Association, Inc.
Articles |
Distal Apolipoprotein C-III Regulatory Elements F to J Act as a General Modular Enhancer for Proximal Promoters That Contain Hormone Response Elements
Synergism Between Hepatic Nuclear Factor-4 Molecules Bound to the Proximal Promoter and Distal Enhancer Sites
the Division of Basic Sciences, Department of Medicine, University of Crete, and Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete, Greece (D.K., I. Talianidis, V.Z.), and the Section of Molecular Genetics, Center for Advanced Biomedical Research, Boston (Mass) University Medical Center (I. Tzameli, M.H.-C., V.Z.).
Correspondence to Vassilis Zannis, Division of Basic Sciences, Department of Medicine, University of Crete, and IMBB, FORTH, Heraklion, Crete, Greece.
Transient transfection assays have shown that the distal apoC-III promoter segments that contain the regulatory elements F to J enhance the strength of the tandemly linked proximal apoA-I promoter 5- to 13-fold in hepatic (HepG2) cells. Activation in intestinal (CaCo-2) cells to levels comparable to those obtained in HepG2 cells requires a larger apoA-I promoter sequence that extends to nucleotide -1500 as well as the presence of hepatic nuclear factor-4 (HNF-4). The distal apoC-III regulatory elements can also enhance 4- to 8-fold the strength of the heterologous apoB promoter in HepG2 and CaCo-2 cells. Finally, these elements in the presence of HNF-4 enhance 14.5- to 18.5-fold the strength of the minimal adenovirus major late promoter linked to two copies of the hormone response element (HRE) AID of apoA-I in both HepG2 and CaCo-2 cells. In vitro mutagenesis of the promoter/enhancer cluster established that the enhancer activity is lost by a mutation in the HRE present in the 3' end of the regulatory element I (-736 to -714) and is reduced significantly by point mutations or deletions in one or more of the regulatory elements F to J of the apoC-III enhancer. The enhancer activity also requires the HREs of the proximal apoA-I promoter. The apoC-III enhancer can also restore the activity of the proximal apoA-I and apoB promoters that have been inactivated by mutations in CCAAT/enhancer binding protein binding sites, indicating that C/EBP may not participate in the synergistic activation of the promoter/enhancer cluster. The findings suggest that the regulatory elements F to J of the apoC-III promoter act as a general modular enhancer that can potentiate the strength of proximal promoters that contain HREs. Such potentiation in the HepG2 cells can be accounted for by synergistic interactions between HNF-4 or other nuclear hormone receptors bound to the proximal and distal HREs and SP1 or other factors bound to the apoC-III enhancer. Additional factors may be required for optimal activity in CaCo-2 cells as well as for the function of this region as an intestinal enhancer.
Key Words: apoC-III enhancer • transcriptional synergism • hepatic and intestinal expression • apoA-I gene regulation • hepatic nuclear factor-4 (HNF-4)
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