title: TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation.
abstract: BACKGROUND
  CCN2/CTGF is an established effector of TGFβ driven responses in diabetic nephropathy. We have identified an interaction between CCN2 and TGFβ leading to altered phenotypic differentiation and inhibited cellular migration. Here we determine the gene expression profile associated with this phenotype and define a transcriptional basis for differential actin related gene expression and cytoskeletal function.
  
  
  RESULTS
  From a panel of genes regulated by TGFβ and CCN2, we used co-inertia analysis to identify and then experimentally verify a subset of transcription factors, E2F1 and CREB, that regulate an expression fingerprint implicated in altered actin dynamics and cell hypertrophy. Importantly, actin related genes containing E2F1 and CREB binding sites, stratified by expression profile within the dataset. Further analysis of actin and cytoskeletal related genes from patients with diabetic nephropathy suggests recapitulation of this programme during the development of renal disease. The Rho family member Cdc42 was also found uniquely to be activated in cells treated with TGFβ and CCN2; Cdc42 interacting genes were differentially regulated in diabetic nephropathy.
  
  
  CONCLUSIONS
  TGFβ and CCN2 attenuate CREB and augment E2F1 transcriptional activation with the likely effect of altering actin cytoskeletal and cell growth/hypertrophic gene activity with implications for cell dysfunction in diabetic kidney disease. The cytoskeletal regulator Cdc42 may play a role in this signalling response.
authors.affiliation: UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Noel
authors.initials: N
authors.lastname: Faherty
authors.forename: Helen
authors.initials: H
authors.lastname: O'Donovan
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Stephen
authors.initials: S
authors.lastname: Madden
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: McKay
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: John
authors.initials: J
authors.lastname: Crean
mesh_terms: D000199:Actins / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006984:Hypertrophy / Q000235:genetics; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D060066:Protein Interaction Maps; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D017362:Cyclic AMP Response Element-Binding Protein; D050687:E2F1 Transcription Factor; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020764:cdc42 GTP-Binding Protein
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