title: FosB regulates stretch-induced expression of extracellular matrix proteins in smooth muscle.
abstract: Fibroproliferative remodeling in smooth muscle-rich hollow organs is associated with aberrant extracellular matrix (ECM) production. Although mechanical stimuli regulate ECM protein expression, the transcriptional mediators of this process remain poorly defined. Previously, we implicated AP-1 as a mediator of smooth muscle cell (SMC) mechanotransduction; however, its role in stretch-induced ECM regulation has not been explored. Herein, we identify a novel role for the AP-1 subunit FosB in stretch-induced ECM expression in SMCs. The DNA-binding activity of AP-1 increased after stretch stimulation of SMCs in vitro. In contrast to c-Jun and c-fos, which are also activated by the SMC mitogen platelet-derived growth factor, FosB was only activated by stretch. FosB silencing attenuated the expression of the profibrotic factors tenascin C (TNC) and connective tissue growth factor (CTGF), whereas forced expression of Jun~FosB stimulated TNC and CTGF promoter activity. Chromatin immunoprecipitation revealed enrichment of AP-1 at the TNC and CTGF promoters. Bladder distension in vivo enhanced nuclear localization of c-jun and FosB. Finally, the distension-induced expression of TNC and CTGF in the detrusor smooth muscle of bladders from wild-type mice was significantly attenuated in FosB-null mice. Together, these findings identify FosB as a mechanosensitive regulator of ECM production in smooth muscle.
authors: Urological Diseases Research Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
authors: Aruna
authors: A
authors: Ramachandran
authors: Edward M
authors: EM
authors: Gong
authors: Kristine
authors: K
authors: Pelton
authors: Sandeep A
authors: SA
authors: Ranpura
authors: Michelle
authors: M
authors: Mulone
authors: Abhishek
authors: A
authors: Seth
authors: Pablo
authors: P
authors: Gomez
authors: Rosalyn M
authors: RM
authors: Adam
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051379:Mice; D009126:Muscle Relaxation / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D034741:RNA, Small Interfering / Q000502:physiology; D019063:Tenascin / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D019063:Tenascin; D018808:Transcription Factor AP-1; D055513:Connective Tissue Growth Factor