Endothelin-1 gene regulation

Abstract

Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1). Studies conducted on a variety of cell types have identified key transcription factors that govern edn1 expression. With few exceptions, the cis-acting elements bound by these factors have been mapped in the edn1 regulatory region. Recent evidence has revealed new roles for some factors originally believed to regulate edn1 in a tissue or hormone-specific manner. In addition, other mechanisms involved in epigenetic regulation and mRNA stability have emerged as important processes for regulated edn1 expression. The goal of this review is to provide a comprehensive overview of the specific factors and signaling systems that govern edn1 activity at the molecular level.

Figure 1.

Overview of ET-1 physiology. Major physiological actions of ET-1 are summarized in the text and have been recently reviewed in brain (–4), eye (5, 6), heart (–10), lung (, –14), vasculature (, –19), kidney (3, 18, 20, 21), liver (23), ovaries (24), cancer (3, 25), immune function (3, 9, 10, 26), bone (3), and embryogenesis (3, 27). Structure of ET-1 was rendered from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB 1T7H).

Figure 2.

Overview of ET-1 synthesis. Intron-exon structure and RNA processing pathway are indicated for the edn1 gene. Translation yields preproET-1 that is processed in sequential proteolytic steps to generate ET-1. Structure of ET-1 contains 2 disulfide bridges and was rendered from the RCSB Protein Data Bank (PDB 1T7H).

Figure 3.

Summary of edn1 promoter regulation. A) cis-acting elements of the edn1 promoter are shown along with the known regulatory pathways and factors that mediate edn1 gene activity. Although many of these signaling pathways are known to overlap, only the factors documented in the signal transduction pathway leading from the given stimulus to the edn1 gene are shown. Nucleotide positions are numbered relative to the primary transcriptional start site and correspond to the human edn1 gene (NCBI accession no. NC_000006). Signals that increase or decrease edn1 are shown in green and red, respectively. Akt, protein kinase B; AP-1, activator protein-1; ALK5, activin receptor-like kinase 5; ERK1/2, extracellular signal-regulated kinase 1/2; FOXO1, forkhead box O1; GR, glucocorticoid receptor; GSK3β, glycogen synthase kinase 3β; HIF-1, hypoxia inducible factor-1; IκB, inhibitor of κB; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen activate protein kinase; MR, mineralocorticoid receptor; NADPH, nicotinamide adenine dinucleotide phosphate; Per1, period 1; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; TAFs, TATA associated factors; TBP, TATA binding protein; TGFβ, transforming growth factor β; TNF-α, tumor necrosis factor α; RNA pol, RNA polymerase; RhoA, Ras homology kinase A; Smad, mothers against decapentaplegic homologue; Vezf1, vascular endothelial zinc finger binding protein f1. B) Alignment of the edn1 proximal promoter from Homo sapiens, Pan troglodytes, Macaca mulatta, Bos taurus, Equus caballus, Canis familiaris, Sus scrofa, Rattus norvegicus, and Mus musculus. Alignment logo was created using WebLogo software (63). Overall height of each nucleotide indicates the relative conservation at that position measured in bits, with 2.0 bits representing 100% conservation in all 9 species analyzed.