Egr-1: is it always immediate and early?

摘要: The early growth response gene product (Egr-1) is a zinc finger transcription factor (1, 2) first identified because of its characteristic pattern expression following exposure cells to mediators associated with and differentiation. Egr-1 (also called Zif268, NGF1-A, Krox24, or TIS8) has been termed an immediate-early protein, based on the brisk kinetics induction, within minutes stimulus, rapid decay, often hours. The initial association development suggested that it might act in cell differentiation, culture studies indicated crucial role for promoting differentiation along macrophage lineage (3). However, generation Egr-1–null mice by S. Lee colleagues provided new perspective biology (4). Monocyte they found, unaffected deletion gene, knockout animals appear normal exception infertility homozygous null females These observations physiologic roles only become manifest environmental challenge. Consistent this possibility, vitro number products — TNFα, ICAM-1, CD44, PDGF A/B chain, TGFβ, M-CSF, among others (5) are induced participate physiological various kinds stress. Recent work from Khachigian important step forward our understanding (6, 7). This group found promoter A chain contains GC-rich element overlapping binding sites Sp1. Under quiescent conditions, these occupied Sp1, which believed be required basal gene. stimulation phorbol ester, levels rise, allowing displace Sp1 region (6). Support vivo relevance Egr-1–mediated comes experiments denuding injury rat aorta; variety target genes endothelium at wound margins (7). Cultured endothelial monolayers subjected analogous mechanical release fibroblast 2 (FGF2), stimulates system (8). Furthermore, DNA-enzyme specifically cleaves mRNA blocks arterial neointima formation carotid angioplasty model (9). Although DNA enzyme approach can difficult interpret human neointimal disease controversial, clearly support vascular (Figure ​(Figure11). Figure 1 Schematic depiction induction vessel wall. especially evident margin, as well migrating proliferating smooth muscle forming ... The pathological blood vessels not limited promotion injury. There unexpected during hypoxemia, when triggers deposition fibrin vasculature. Recent have established cause-effect relationships between expression, (10–13) ​(Figure2).2). Mice normobaric hypoxia rapidly induce lung active Egr-1, drives tissue (TF), cell-surface cofactor responsible initiation coagulation. Increased TF, promotes intravascular accumulation (10), observed mononuclear phagocytes cells, same exhibiting increased oxygen deprivation (11). central pathway clear mice, do TF which, consequence, remain free deposits under conditions. Figure 2 Schematic wall phagocytes/macrophages hypoxemia. Oxygen causes thereby activating downstream best-characterized biosynthetic adaptation involves hypoxia-inducible factor-1 (HIF-1), critical survival oxygen-scarce environment (14). hypoxia-triggered involving independent HIF-1 appears through activation protein kinase C isoform βII (PKCβII) decline. initiates signaling cascade activates Elk-1 (11, 12). model, expressed hypoxic carry PKCβ, although retain HIF-1–dependent responses (13). novel may relevant pathobiology ischemic injury. In each studies, acute physical hypoxia, but, current issue JCI, McCaffrey demonstrate sustained atherosclerosis, chronic condition (15). investigators harvested RNA fibrous cap endarterectomy samples used cDNA array analyze changes disease. They demonstrated approximately 5-fold increase lesions, compared adjacent media. Crucially, lesions also showed known transcripts, such contribute process. In addition, confirmed accumulates postnatal atherosclerosis-prone enriched atherosclerotic cells. At juncture, represent nothing more than association, provocative one, atherogenic challenge remains establish pertinent outcome, availability likely purpose, identification physiologically targets Egr-1. It will dissect regulation activity, including inducible corepressor NAB2 (16), determine if other members family atherogenesis hyperplasia thrombosis. If implicate pathogenetic factor, apparent well-being (4) suggests function could inhibited therapeutic purposes little ill effect.