ABSTRACT

Liver-specific expression of the apolipoprotein AI (apoAI) gene is mediated by transcription factors bound to three sites (A, B, and C) in the apoAI enhancer. Sites A and C bind various members of the nuclear receptor superfamily, including the orphan nuclear receptor apolipoprotein regulatory protein-1 (ARP-1); site B binds the liver-enriched factor hepatic nuclear factor-3. The immediate early growth response factor (Egr-1), which is transiently expressed in various pathophysiologic states of the liver, activates the apoAI enhancer and overcomes ARP-1-mediated repression of the enhancer in hepatoblastoma HepG2 cells. Deletion mapping analysis revealed two Egr-1 binding sites, E1 and E2, flanking site A. Egr-1 bound efficiently to both E1 and E2. Sp1 in HepG2 nuclear extracts bound to E2 but not E1. In HepG2 cells, E1 functioned as an Egr-1 response element, whereas E2 had high basal activity and was not further induced by Egr-1. Mutations that prevent Egr-1 binding to the apoAI enhancer abolished its responsiveness to Egr-1, while they had only minor effects on its constitutive activity. These mutations also diminished the ability of Egr-1 to overcome ARP-1-mediated repression. Elimination of transcription factor binding to sites A, B, or C reduced enhancer activity without affecting Egr-1-dependent activation. We argue that Egr-1 is recruited to the apoAI enhancer complex under unusual circumstances, such as those prevailing during liver regeneration, to maintain apoAI transcription levels by overriding prior transcriptional controls.

FOOTNOTES

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§

Present address: Arthritis Center, Boston University School of Medicine, Boston, MA 02118.

¶

To whom correspondence should be addressed. Tel.: 914-732-4778; Fax: 914-732-5665.

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The abbreviations used are: apoAI, apolipoprotein AI; HNF, hepatic nuclear factor; ARP-1, apolipoprotein regulatory protein-1; Egr, early growth response; CMV, cytomegalovirus; C/EBP, CAAT/enhancer binding protein; EMSA, electrophoretic mobility shift assay; CAT, chloramphenicol acetyltransferase.

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E. Kilbourne, R. Widom, D. C. Harnish, S. Malik, and S. K. Karathanasis, unpublished results.

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