title: Estrogen modulates plasminogen promoter activity.
abstract: Postmenopausal women treated with estrogen hormone replacement therapy and female patients with hypoplasminogenemia receiving oral contraceptives show increasing plasminogen (PLG) concentrations. The elevated PLG levels are in contrast to the estrogen dependent decline of lipoptrotein(a) [Lp(a)], whose main protein component apolipoprotein(a) [APO(a)] is highly homologous to PLG in protein and gene structure and is also located in its immediate vicinity on chromosome 6q26. The intergenic region between both genes comprises several transcription-regulatory regions with enhancer sequences that increase the basal activity of the PLG core promoter. Using luciferase reporter assays we demonstrate that the minimal PLG promoter is insensitive to estrogen. However, an estrogen response element located 11.5 kb upstream of the PLG transcription start site is able to convey a dramatic estrogen-dependent elevation of PLG-minimal promoter driven reporter gene expression. In contrast, the activating effect of two additional enhancer elements, among them an DNase I hypersensitivity region that has been shown to regulate the APO(a) minimal promoter activity, is abrogated by estrogen. Thus, the identified estrogen-responsive elements provide a gene and tissue specific framework by which PLG expression is regulated and whose activity is orchestrated by yet unknown accessory factors.
authors.affiliation: Hospital for Children and Adolescents, Centre for Pediatric Research, University of Leipzig, Germany. Electronic address: louise.kobelt@medizin.uni-leipzig.de.
authors.forename: Louise
authors.initials: L
authors.lastname: Kobelt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klammt
authors.forename: Katrin
authors.initials: K
authors.lastname: Tefs
authors.forename: Volker
authors.initials: V
authors.lastname: Schuster
mesh_terms: D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D010958:Plasminogen / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
chemical_list: D004967:Estrogens; D010958:Plasminogen
keywords: APO(a); DH; DNase hypersensitivity; ERE; Enhancer element; Estrogen; Estrogen receptor; Lp(a); PLG; Plasminogen; Promoter; TSS; Transcription; apolipoprotein(a); estrogen-response element; lipoptrotein(a); plasminogen; transcription start site