Pin1 protein regulates Smad protein signaling and pulmonary fibrosis. J Biol Chem 2012 Jul 06;287(28):23294-305
Date
05/23/2012Pubmed ID
22613712Pubmed Central ID
PMC3390608DOI
10.1074/jbc.M111.313684Scopus ID
2-s2.0-84863611032 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Shen ZJ, Braun RK, Hu J, Xie Q, Chu H, Love RB, Stodola LA, Rosenthal LA, Szakaly RJ, Sorkness RL, Malter JSMESH terms used to index this publication - Major topics in bold
Active Transport, Cell NucleusAnimals
Bleomycin
Cell Nucleus
Cells, Cultured
Cytoplasm
Fibroblasts
Immunoblotting
Immunoprecipitation
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Mutation
NIMA-Interacting Peptidylprolyl Isomerase
Peptidylprolyl Isomerase
Phosphorylation
Protein Binding
Pulmonary Fibrosis
RNA Interference
Signal Transduction
Smad3 Protein
Smad6 Protein
Transforming Growth Factor beta1
