title: Cysteine-rich protein 1 is regulated by transforming growth factor-β1 and expressed in lung fibrosis.
abstract: Transforming growth factor-β (TGF-β) is a diverse cytokine regulating growth, apoptosis, differentiation, adhesion, invasion, and extracellular matrix production. Dysregulation of TGF-β is associated with fibrotic disorders and epithelial-mesenchymal transition, and has been linked with idiopathic pulmonary fibrosis (IPF). Cysteine-rich protein 1 (CRP1) is a small LIM-domain containing protein involved in smooth muscle differentiation. Here, we show that TGF-β1 increases the expression of CRP1 protein and that CRP1 levels increase in a biphasic fashion. A rapid transient (15-45 min) increase in CRP1 is followed by a subsequent, sustained increase in CRP1 a few hours afterwards that lasts several days. We find that TGF-β1 regulates the expression of CRP1 through Smad and non-conventional p38 MAPK signaling pathways in a transcription-independent manner and that the induction occurs concomitant with an increase in myofibroblast differentiation. Using CRP1 silencing by shRNA, we identify CRP1 as a novel factor mediating cell contractility. Furthermore, we localize CRP1 to fibroblastic foci in IPF lungs and find that CRP1 is significantly more expressed in IPF as compared to control lung tissue. The results show that CRP1 is a novel TGF-β1 regulated protein that is expressed in fibrotic lesions and may be relevant in the IPF disease.
authors: Molecular Cancer Biology Program and Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Päivi M
authors: PM
authors: Järvinen
authors: Marjukka
authors: M
authors: Myllärniemi
authors: Hester
authors: H
authors: Liu
authors: Henna M
authors: HM
authors: Moore
authors: Outi
authors: O
authors: Leppäranta
authors: Kaisa
authors: K
authors: Salmenkivi
authors: Katri
authors: K
authors: Koli
authors: Leena
authors: L
authors: Latonen
authors: Arja M
authors: AM
authors: Band
authors: Marikki
authors: M
authors: Laiho
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D048430:Cell Shape; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D034622:RNA Interference; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C486181:CRIP1 protein, human; D002352:Carrier Proteins; D060588:LIM Domain Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases