title: A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency.
abstract: Epidemiological data, animal studies and interventional studies provide evidence for a potential chemopreventive effect of selenium during development of colorectal cancer. The human glycoprotein Selenoprotein P (SeP) contains up to 50% of plasma selenium content. SeP is expressed in the gastrointestinal tract and the liver, where its expression is downregulated by various proinflammatory cytokines (Il1beta, TGFbeta, IFNgamma). Previously, we have demonstrated dramatically reduced SeP expression in human colon adenomas. Here, we have identified a complex (A)4-C-(A)4-GG-(A)8-GCT-(TC)5-(T)17 (bp -429 to bp - 477) repeat structure within the SeP promoter and we have analysed this regulatory DNA sequence with respect to polymorphisms, genomic instability and functional relevance to promoter activity. As opposed to the (TC)5 variant we identified a novel (TC)3 polymorphism within this repeat in the general population, which conferred significantly reduced basal promoter activity to reporter gene constructs in HepG2 cells. Allelic distribution of this (TC)(n) element was similar in colon carcinoma patients and healthy controls. Additionally, we observed genetic instability within the (T)17 repeat motif in colon cancers of the mutator phenotype. This instability of the (T)17 repeat had no effect on basal promoter activity in reporter gene assays. In conclusion, we characterised a complex repeat structure within the SeP promoter that may be of functional relevance to SeP gene expression. Further studies on the effect of different SeP promoter genotypes on SeP protein expression and disease susceptibility are needed.
authors.affiliation: Medizinische Poliklinik der Universität Würzburg, Germany. al-taie.medpoli@mail.uni-wuerzburg.de
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Al-Taie
authors.forename: Jochen
authors.initials: J
authors.lastname: Seufert
authors.forename: Hubert
authors.initials: H
authors.lastname: Mörk
authors.forename: Holger
authors.initials: H
authors.lastname: Treis
authors.forename: Birgit
authors.initials: B
authors.lastname: Mentrup
authors.forename: Andreas
authors.initials: A
authors.lastname: Thalheimer
authors.forename: Petr
authors.initials: P
authors.lastname: Starostik
authors.forename: Josef
authors.initials: J
authors.lastname: Abel
authors.forename: Michael
authors.initials: M
authors.lastname: Scheurlen
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
mesh_terms: D020137:Base Pair Mismatch; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D012643:Selenium / Q000097:blood; D051149:Selenoprotein P; D051140:Selenoproteins
chemical_list: D017931:DNA Primers; D011506:Proteins; D051149:Selenoprotein P; D051140:Selenoproteins; D012643:Selenium