title: Expression of tumor-promoting Cyr61 is regulated by hTRA2-β1 and acidosis.
abstract: The matricellular protein Cysteine rich 61 (Cyr61) displays a remarkable diversity of multiple cellular functions involved in significant physiologic and pathologic processes. Cyr61 is known as an important player in tumor progression, promoting neovascularization and metastasis. Our prior investigations elucidated an oxygen-dependent Cyr61 alternative splicing process characterized by retention of its intron 3, regulating its biological function in a hypoxia-driven on/off switch mechanism. In this work, we identified extracellular acidosis as a potent inducer for altered Cyr61 alternative splicing pattern regulating Cyr61 expression. Intriguingly, splicing factor hTRA2-beta1 displayed an opposite effect on Cyr61 expression. Nuclear hTRA2-beta1 protein expression was found markedly reduced under acidic conditions. In keeping with these conclusions, we show that hTRA2-beta1 can specifically bind a 'GAAG' motif in Cyr61 exon 3 RNA, that the splicing factor displays acidosis-dependent protein localization in cellular compartments, and shRNA-mediated hTRA2-beta1 knock-down triggers the same effects on Cyr61 alternative splicing like acidosis or hypoxia. Our findings strongly support the hypothesis of a specific regulation of Cyr61 expression by hTRA2-beta1.
authors: Gynaecological Hospital, Freiburg University Medical Center, Hugstetterstr. 55, D-79106 Freiburg, Germany. marc.hirschfeld@uniklinik-freiburg.de
authors: Marc
authors: M
authors: Hirschfeld
authors: Markus
authors: M
authors: Jaeger
authors: Emanuele
authors: E
authors: Buratti
authors: Cristiana
authors: C
authors: Stuani
authors: Johannes
authors: J
authors: Grueneisen
authors: Gerald
authors: G
authors: Gitsch
authors: Elmar
authors: E
authors: Stickeler
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D055515:Cysteine-Rich Protein 61 / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C097083:TRA2B protein, human; D000068103:Serine-Arginine Splicing Factors