title: Dysbindin is a potent inducer of RhoA-SRF-mediated cardiomyocyte hypertrophy.
abstract: Dysbindin is an established schizophrenia susceptibility gene thoroughly studied in the context of the brain. We have previously shown through a yeast two-hybrid screen that it is also a cardiac binding partner of the intercalated disc protein Myozap. Because Dysbindin is highly expressed in the heart, we aimed here at deciphering its cardiac function. Using a serum response factor (SRF) response element reporter-driven luciferase assay, we identified a robust activation of SRF signaling by Dysbindin overexpression that was associated with significant up-regulation of SRF gene targets, such as Acta1 and Actc1. Concurrently, we identified RhoA as a novel binding partner of Dysbindin. Further phenotypic and mechanistic characterization revealed that Dysbindin induced cardiac hypertrophy via RhoA-SRF and MEK1-ERK1 signaling pathways. In conclusion, we show a novel cardiac role of Dysbindin in the activation of RhoA-SRF and MEK1-ERK1 signaling pathways and in the induction of cardiac hypertrophy. Future in vivo studies should examine the significance of Dysbindin in cardiomyopathy.
authors.affiliation: Department of Internal Medicine III, University Medical Center Schleswig-Holstein, D-24105 Kiel, Germany.
authors.forename: Ashraf Yusuf
authors.initials: AY
authors.lastname: Rangrez
authors.forename: Alexander
authors.initials: A
authors.lastname: Bernt
authors.forename: Reza
authors.initials: R
authors.lastname: Poyanmehr
authors.forename: Violetta
authors.initials: V
authors.lastname: Harazin
authors.forename: Inka
authors.initials: I
authors.lastname: Boomgaarden
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
authors.forename: Astrid
authors.initials: A
authors.lastname: Rohrbeck
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; C574928:Dtnbp1 protein, rat; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins; D026362:Serum Response Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein