title: Two isoforms of Sister-Of-Mammalian Grainyhead have opposing functions in endothelial cells and in vivo.
abstract: OBJECTIVE
  Sister-of-Mammalian Grainyhead (SOM) is a member of the Grainyhead family of transcription factors. In humans, 3 isoforms are derived from differential first exon usage and alternative splicing and differ only in their N terminal domain. SOM2, the only variant also present in mouse, induces endothelial cell migration and protects against apoptosis. The functions of the human specific isoforms SOM1 and SOM3 have not yet been investigated. Therefore we wanted to elucidate their functions in endothelial cells.
  
  
  RESULTS
  Overexpression of SOM1 in primary human endothelial cells induced migration, phosphorylation of Akt1 and endothelial nitric oxide synthase, and protected against apoptosis, whereas SOM3 had opposite effects; isoform-specific knockdowns confirmed the disparate effects on apoptosis. After reporter assays demonstrated that both are active transcription factors, microarray analyses revealed that they induce different target genes, which could explain the different cellular effects. Overexpression of SOM3 in zebrafish embryos resulted in increased lethality and severe deformations, whereas SOM1 had no deleterious effect.
  
  
  CONCLUSIONS
  Our data demonstrate that the splice variant-derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes.
authors.affiliation: Molecular Aging Research, IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany. juhae001@uni-duesseldorf.de
authors.forename: Judith
authors.initials: J
authors.lastname: Haendeler
authors.forename: Arne
authors.initials: A
authors.lastname: Mlynek
authors.forename: Nicole
authors.initials: N
authors.lastname: Büchner
authors.forename: Margarete
authors.initials: M
authors.lastname: Lukosz
authors.forename: Martin
authors.initials: M
authors.lastname: Graf
authors.forename: Christopher
authors.initials: C
authors.lastname: Guettler
authors.forename: Sascha
authors.initials: S
authors.lastname: Jakob
authors.forename: Sabrina
authors.initials: S
authors.lastname: Farrokh
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kunze
authors.forename: Christine
authors.initials: C
authors.lastname: Goy
authors.forename: Francisca
authors.initials: F
authors.lastname: Guardiola-Serrano
authors.forename: Heiner
authors.initials: H
authors.lastname: Schaal
authors.forename: Miriam
authors.initials: M
authors.lastname: Cortese-Krott
authors.forename: René
authors.initials: R
authors.lastname: Deenen
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.forename: Christoph
authors.initials: C
authors.lastname: Winkler
authors.forename: Joachim
authors.initials: J
authors.lastname: Altschmied
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; D020033:Protein Isoforms; D014157:Transcription Factors; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; cell movement; human umbilical vein endothelial cells; nitric oxide; sister-of-mammalian grainyhead protein, human; transcription factors; zebrafish