Pin1 protein regulates smad protein signaling and pulmonary fibrosis

Zhong Jian Shen, Ruedi K. Braun, Jie Hu, Qifa Xie, Haiyan Chu, Robert B. Love, Levi A. Stodola, Louis A. Rosenthal, Renee J. Szakaly, Ronald L. Sorkness, James S. Malter

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)23294-23305
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number28
DOIs
StatePublished - Jul 6 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shen, Z. J., Braun, R. K., Hu, J., Xie, Q., Chu, H., Love, R. B., Stodola, L. A., Rosenthal, L. A., Szakaly, R. J., Sorkness, R. L., & Malter, J. S. (2012). Pin1 protein regulates smad protein signaling and pulmonary fibrosis. Journal of Biological Chemistry, 287(28), 23294-23305. https://doi.org/10.1074/jbc.M111.313684