Involvement of Early Growth Response Factor Egr-1 in Apolipoprotein AI Gene Transcription

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. Erg-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 Erg-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.

Effects of ketoacidosis on rat apolipoprotein A1 gene expression: a link with acidosis but not with ketones

“…Tyrosine kinase inhibitors substantially reduce the effect of acidosis on transcription, but the actual kinases involved in the signal transduction cascade remain to be elucidated. Interestingly, the apoAI gene promoter has an EGR-1 binding site (Kilbourne et al 1995) which may be responsible for the pH effect described here. Acidosis may  7.…”

Transcriptional Induction of Rat Liver Apolipoprotein A‐I Gene Expression by Glucocorticoids Requires the Glucocorticoid Receptor and a Labile Cell‐Specific Protein

“…This transcription factor would activate apoA-I gene transcription through sequences located in the proximal-promoter region (the first 250 bp). Several transcription factors, such as HNF4, PPAR (peroxisome-proliferator-activated receptor), RXR (retinoid X receptor), Arp-1, HNF3 and Egr-I [34,54,[59][60][61][62], have been shown to interact with different sites in the apoA-I gene promoter. However, it is unlikely that factors that bind to the apoA-I A site mediate the responsiveness to glucocorticoids, since dexamethasone was unable to stimulate transcription from the rat apoA-I A site cloned upstream of the minimal apoA-I promoter (data not shown).…”

Apolipoprotein A-1 is a negative target of v-Jun overexpression

“…Gene expression of apolipoprotein A-1 is controlled by a number of dierent positive and negative transcriptional control elements. Evidence exists linking glucocorticoids (Varma et al, 1992;Taylor et al, 1996), members of the retinoic acid receptor family (Rottman et al, 1991;Widom et al, 1992), HNF4 (Ge et al, 1994) and Egr-1 (Kilbourne et al, 1995) as positive regulatory factors of apolipoprotein A-1 gene transcription. The glucocorticoid receptor does not bind directly to the apolipoprotein A1 promoter and therefore appears to exert its positive eect through an indirect mechanism (Taylor et al, 1996).…”