title: Pin1 protein regulates Smad protein signaling and pulmonary fibrosis.
abstract: Interstitial pulmonary fibrosis is caused by the excess production of extracellular matrix (ECM) by Fb in response to TGF-β1. Here, we show that the peptidyl-prolyl isomerase Pin1 modulates the production of many pro- and antifibrogenic cytokines and ECM. After acute, bleomycin injury, Pin1(-/-) mice showed reduced, pulmonary expression of collagens, tissue inhibitors of metalloproteinases, and fibrogenic cytokines but increased matrix metalloproteinases, compared with WT mice, despite similar levels of inflammation. In primary fibroblasts, Pin1 was required for TGF-β-induced phosphorylation, nuclear translocation, and transcriptional activity of Smad3. In Pin1(-/-) cells, inhibitory Smad6 was found in the cytoplasm rather than nucleus. Smad6 knockdown in Pin1(-/-) fibroblasts restored TGF-β-induced Smad3 activation, translocation, and target gene expression. Therefore, Pin1 is essential for normal Smad6 function and ECM production in response to injury or TGF-β and thus may be an attractive therapeutic target to prevent excess scarring in diverse lung diseases.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Shen
authors.forename: Ruedi K
authors.initials: RK
authors.lastname: Braun
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Qifa
authors.initials: Q
authors.lastname: Xie
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chu
authors.forename: Robert B
authors.initials: RB
authors.lastname: Love
authors.forename: Levi A
authors.initials: LA
authors.lastname: Stodola
authors.forename: Louis A
authors.initials: LA
authors.lastname: Rosenthal
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Szakaly
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Sorkness
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001761:Bleomycin; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse