title: High doses of TGF-β potently suppress type I collagen via the transcription factor CUX1.
abstract: Transforming growth factor-β (TGF-β) is an inducer of type I collagen, and uncontrolled collagen production leads to tissue scarring and organ failure. Here we hypothesize that uncovering a molecular mechanism that enables us to switch off type I collagen may prove beneficial in treating fibrosis. For the first time, to our knowledge, we provide evidence that CUX1 acts as a negative regulator of TGF-β and potent inhibitor of type I collagen transcription. We show that CUX1, a CCAAT displacement protein, is associated with reduced expression of type I collagen both in vivo and in vitro. We show that enhancing the expression of CUX1 results in effective suppression of type I collagen. We demonstrate that the mechanism by which CUX1 suppresses type I collagen is through interfering with gene transcription. In addition, using an in vivo murine model of aristolochic acid (AA)-induced interstitial fibrosis and human AA nephropathy, we observe that CUX1 expression was significantly reduced in fibrotic tissue when compared to control samples. Moreover, silencing of CUX1 in fibroblasts from kidneys of patients with renal fibrosis resulted in increased type I collagen expression. Furthermore, the abnormal CUX1 expression was restored by addition of TGF-β via the p38 mitogen-activated protein kinase pathway. Collectively, our study demonstrates that modifications of CUX1 expression lead to aberrant expression of type I collagen, which may provide a molecular basis for fibrogenesis.
authors.affiliation: Renal Medicine, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom. m.fragiadaki05@imperial.ac.uk
authors.forename: Maria
authors.initials: M
authors.lastname: Fragiadaki
authors.forename: Tetsurou
authors.initials: T
authors.lastname: Ikeda
authors.forename: Abigail
authors.initials: A
authors.lastname: Witherden
authors.forename: Roger M
authors.initials: RM
authors.lastname: Mason
authors.forename: David
authors.initials: D
authors.lastname: Abraham
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
mesh_terms: D000818:Animals; D034341:Aristolochic Acids; D002478:Cells, Cultured; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D005355:Fibrosis / Q000188:drug therapy / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein; D014157:Transcription Factors; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; C080632:CUX1 protein, human; D024042:Collagen Type I; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases