title: SMAD-independent down-regulation of caveolin-1 by TGF-β: effects on proliferation and survival of myofibroblasts.
abstract: Transforming growth factor-β (TGF-β) mediates growth-inhibitory effects on most target cells via activation of the canonical SMAD signaling pathway. This growth-inhibitory activity may be coupled with cellular differentiation. Our studies demonstrate that TGF-β1 inhibits proliferation of primary, non-transformed human lung fibroblasts in association with the induction of myofibroblast differentiation. Differentiated myofibroblasts maintain the capacity to proliferate in response to exogenous mitogenic stimuli and are resistant to serum deprivation-induced apoptosis. These proliferative and anti-apoptotic properties of myofibroblasts are related, in part, to the down-regulation of caveolin-1 (Cav-1) by TGF-β1. Cav-1 down-regulation is mediated by early activation of p38 MAPK and does not require SMAD signaling. In contrast, myofibroblast differentiation is dependent on activation of the SMAD pathway, but not on p38 MAPK. Thus, combinatorial signaling by TGF-β1 of myofibroblast differentiation and down-regulation of Cav-1 by SMAD and p38 MAPK pathways, respectively, confer proliferative and apoptosis-resistant properties to myofibroblasts. Selective targeting of this SMAD-independent, p38-MAPK/Cav-1-dependent pathway is likely to be effective in the treatment of pathological conditions characterized by TGF-β signaling and myofibroblast activation.
authors: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.
authors: Yan Y
authors: YY
authors: Sanders
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, United States of America.
authors: Zongbin
authors: Z
authors: Cui
authors: Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, United States of America.
authors: Claude Jourdan
authors: CJ
authors: Le Saux
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, United States of America.
authors: Jeffrey C
authors: JC
authors: Horowitz
authors: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.
authors: Sunad
authors: S
authors: Rangarajan
authors: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.
authors: Ashish
authors: A
authors: Kurundkar
authors: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.
authors: Veena B
authors: VB
authors: Antony
authors: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.
authors: Victor J
authors: VJ
authors: Thannickal
mesh_terms: D051242:Caveolin 1 / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D020935:MAP Kinase Signaling System; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D051785:Smad Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases