Open AccessPost-translational modification of CREB-1 decreases collagen I expression by inhibiting the TGF-β1 signaling pathway in rat hepatic stellate cells
Author(s) -
Xiaoling Deng,
Liang Deng,
Pei Wang,
Ching-Yuan Cheng,
Ke Xu
Publication year - 2016
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2016.5926
Subject(s) - creb , hepatic stellate cell , smad , signal transduction , microbiology and biotechnology , cancer research , transforming growth factor , transforming growth factor beta , biology , cyclic amp response element binding protein , chemistry , cyclic adenosine monophosphate , transcription factor , endocrinology , biochemistry , receptor , gene
Liver fibrosis is a reversible wound‑healing response to liver damage. Following liver injury, activated hepatic stellate cells (HSCs) cause excessive deposition of collagen and other components of the extracellular matrix, which may eventually impair liver function. Transforming growth factor‑β1 (TGF‑β1) is critical for the development of liver fibrosis, and acts by activating HSCs, stimulating matrix deposition and inducing other profibrotic responses. Certain studies have demonstrated that the transcription factor, cyclic adenosine monophosphate (cAMP)‑response element binding protein‑1 (CREB‑1) is important in the inhibition of fibrosis; however, the underlying mechanism remains to be elucidated. The present study hypothesized that CREB‑1 inhibits fibrosis via blocking the TGF‑β1 signaling pathway in HSCs. Treatment with the cAMP‑elevating agent, forskolin stimulated CREB‑1 phosphorylation and transcription activation in HSCs. In addition, treatment with the histone deacetylase inhibitor, trichostatin A extended CREB‑1 phosphorylation. The present study used a pRSV‑CREB‑1 expression vector to upregulate CREB‑1 gene expression. The results indicated that activated CREB‑1 reduced TGF‑β1‑stimulated expression of collagen I, activated Smad2/3 and upregulated expression of Smad7. In addition, activated CREB‑1 attenuated the activation of extracellular signal‑regulated kinase 1/2 induced by TGF‑β1, expression of Ras homolog gene family, member A (RhoA) and Rho‑associated coiled‑coil containing protein kinase 1. Thus, post‑translational modification of CREB‑1 inhibited the profibrotic effects of TGF‑β1 in HSCs via Smad‑dependent and ‑independent signaling pathways.