18 research outputs found
Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling
Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis▿
Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-α) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-α stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1α and/or HIF-2α, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-α activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA
Sustained Smad2 Phosphorylation Is Required for Myofibroblast Transformation in Response to TGF-β
Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin
Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation
Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation
Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia
Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis