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Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1.

Authors: Hu, B  Wu, Z  Hergert, P  Henke, CA  Bitterman, PB  Phan, SH 
Citation: Hu B, etal., Am J Pathol. 2013 Jan;182(1):71-83. doi: 10.1016/j.ajpath.2012.09.004.
Pubmed: (View Article at PubMed) PMID:23260200
DOI: Full-text: DOI:10.1016/j.ajpath.2012.09.004

Poly(ADP-ribosyl)ation (PARylation) is a post-translational protein modification effected by enzymes belonging to the poly(ADP-ribose) polymerase (PARP) superfamily, mainly by PARP-1. The key acceptors of poly(ADP-ribose) include PARP-1 itself, histones, DNA repair proteins, and transcription factors. Because many of these factors are involved in the regulation of myofibroblast differentiation, we examined the role of PARylation on myofibroblast differentiation. Overexpression of PARP-1 with an expression plasmid activated expression of the alpha-SMA gene (Acta2), a marker of myofibroblast differentiation in lung fibroblasts. Suppression of PARP-1 activity or gene expression with PARP-1 inhibitors or siRNA, respectively, had the opposite effect on these cells. PARP-1-deficient cells also had reduced alpha-SMA gene expression. DNA pyrosequencing identified hypermethylated regions of the alpha-SMA gene in PARP-1-deficient cells, relative to wild-type cells. Interestingly, and of potential relevance to human idiopathic pulmonary fibrosis, PARP activity in lung fibroblasts isolated from idiopathic pulmonary fibrosis patients was significantly higher than that in cells isolated from control subjects. Furthermore, PARP-1-deficient mice exhibited reduced pulmonary fibrosis in response to bleomycin-induced lung injury, relative to wild-type controls. These results suggest that PARylation is important for myofibroblast differentiation and the pathogenesis of pulmonary fibrosis.


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RGD Object Information
RGD ID: 10413908
Created: 2015-12-01
Species: All species
Last Modified: 2015-12-01
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.