title: Unique and Redundant Functions of p70 Ribosomal S6 Kinase Isoforms Regulate Mesenchymal Cell Proliferation and Migration in Pulmonary Fibrosis.
abstract: The p70 ribosomal S6 kinase (p70S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with pulmonary fibrogenesis. Two isoforms of the p70S6K have been identified (S6K1 and S6K2), but their relative contributions in mediating pulmonary fibrosis are unknown. To interrogate the roles of the p70S6K isoforms, we overexpressed transforming growth factor (TGF)-α in mice deficient for the S6K1 or S6K2 genes and measured changes in lung histology, morphometry, total lung collagen, lung function, and proliferation between wild-type and isoform-deficient mice. Deficiency of S6K1, but not S6K2, had a significant effect on reducing proliferation in subpleural fibrotic lesions during TGF-α-induced fibrosis. Migration was significantly decreased in mesenchymal cells isolated from the lungs of S6K1 knockout mice compared with wild-type or S6K2 knockout mice. Conversely, increases in subpleural thickening were significantly decreased in S6K2-deficient mice compared with wild type. Deficiency of S6K2 significantly reduced phosphorylation of the downstream S6 ribosomal protein in lung homogenates and isolated mesenchymal cells after TGF-α expression. However, deficiency of neither isoform alone significantly altered TGF-α-induced collagen accumulation or lung function decline in vivo. Furthermore, deficiency in neither isoform prevented changes in collagen accumulation or lung compliance decline after administration of intradermal bleomycin. Together, these findings demonstrate that the p70S6K isoforms have unique and redundant functions in mediating fibrogenic processes, including proliferation, migration, and S6 phosphorylation, signifying that both isoforms must be targeted to modulate p70S6K-mediated pulmonary fibrosis.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Madala
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Vishwaraj
authors.initials: V
authors.lastname: Sontake
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edukulla
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Davidson
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
mesh_terms: D000818:Animals; D001761:Bleomycin; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008648:Mesoderm / Q000473:pathology*; D008822:Mice, Transgenic; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D019394:Ki-67 Antigen; D016211:Transforming Growth Factor alpha; D001761:Bleomycin; D003094:Collagen; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: mammalian target of rapamycin; p70 ribosomal S6 kinase; pleural disease; pulmonary fibrosis