FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis
Open Access
- 7 May 2018
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 128 (6), 2389-2405
- https://doi.org/10.1172/jci87631
Abstract
While the transcription factor forkhead box M1 (FOXM1) is well known as a proto-oncogene, its potential role in lung fibroblast activation has never been explored. Here, we show that FOXM1 is more highly expressed in fibrotic than in normal lung fibroblasts in humans and mice. FOXM1 was required not only for cell proliferation in response to mitogens, but also for myofibroblast differentiation and apoptosis resistance elicited by TGF-β. The lipid mediator PGE2, acting via cAMP signaling, was identified as an endogenous negative regulator of FOXM1. Finally, genetic deletion of FOXM1 in fibroblasts or administration of the FOXM1 inhibitor Siomycin A in a therapeutic protocol attenuated bleomycin-induced pulmonary fibrosis. Our results identify FOXM1 as a driver of lung fibroblast activation and underscore the therapeutic potential of targeting FOXM1 for pulmonary fibrosis.Keywords
This publication has 79 references indexed in Scilit:
- Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repairBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013
- FoxO3a (Forkhead Box O3a) Deficiency Protects Idiopathic Pulmonary Fibrosis (IPF) Fibroblasts from Type I Polymerized Collagen Matrix-Induced Apoptosis via Caveolin-1 (cav-1) and FasPLOS ONE, 2013
- Thiazole Antibiotics Siomycin a and Thiostrepton Inhibit the Transcriptional Activity of FOXM1Frontiers in Oncology, 2013
- Mechanisms of fibrosis: therapeutic translation for fibrotic diseaseNature Medicine, 2012
- Mesenchymal-Specific Deletion of C/EBPβ Suppresses Pulmonary FibrosisThe American Journal of Pathology, 2012
- Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosisThe International Journal of Biochemistry & Cell Biology, 2012
- Foxm1 transcription factor is required for macrophage migration during lung inflammation and tumor formationOncogene, 2011
- A robust and high-throughput Cre reporting and characterization system for the whole mouse brainNature Neuroscience, 2009
- The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?The International Journal of Biochemistry & Cell Biology, 2008
- An N-terminal inhibitory domain modulates activity of FoxM1 during cell cycleOncogene, 2007