Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts.

Abstract

Transforming growth factor beta (TGF-beta) stimulates reactive oxygen species (ROS) production in various cell types, which mediates many of the effects of TGF-beta. The molecular mechanisms whereby TGF-beta increases ROS production and ROS modulate the signaling processes of TGF-beta, however, remain poorly defined. In this study, we show that TGF-beta1 stimulates NADPH oxidase 4 (Nox4) expression and ROS generation in the nucleus of murine embryo fibroblasts (NIH3T3 cells). This is associated with an increase in protein thiol modification and inactivation of MAPK phosphatase 1 (MKP-1), a nuclear phosphatase. Furthermore, knockdown of MKP-1 using small interfering RNA enhances TGF-beta1-induced phosphorylation of JNK and p38 as well as the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-beta-responsive gene involved in the pathogenesis of many diseases. Knockdown of Nox4 with Nox4 small interfering RNA, on the other hand, reduces TGF-beta1-stimulated ROS production, p38 phosphorylation, and PAI-1 expression. TGF-beta also increased the nuclear level of Nox4 protein as well as PAI-1 expression in human lung fibroblasts (CCL-210 cells), suggesting that TGF-beta may induce PAI-1 expression by a similar mechanism in human lung fibroblasts. In summary, in this study we have identified nuclear MAPK phosphatase MKP-1 as a novel molecular target of ROS in TGF-beta signaling pathways. Our data suggest that increased generation of ROS by Nox4 mediates TGF-beta1-induced PAI-1 gene expression at least in part through oxidative modification and inhibition of MKP-1 leading to a sustained activation of JNK and p38 MAPKs.

DOI: 10.1074/jbc.M110.111732

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@article{Liu2010OxidativeMO, title={Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts.}, author={Rui-ming Liu and Jinah Choi and Jian-He Wu and Kimberly A Gaston Pravia and Karen M. Lewis and Jeffrey D. Brand and N S Reyes Mochel and David M Krzywanski and J. David Lambeth and James S. Hagood and Henry Jay Forman and Victor J Thannickal and Edward M. Postlethwait}, journal={The Journal of biological chemistry}, year={2010}, volume={285 21}, pages={16239-47} }