title: SOCS-2 interferes with myotube formation and potentiates osteoblast differentiation through upregulation of JunB in C2C12 cells.
abstract: Suppressor of cytokine signaling (SOCS)-2 regulates normal postnatal growth and its deficiency in mice causes gigantism with increased bone length and proportional enlargement in skeletal muscles. Using C2C12 mesenchymal precursor cell line as a model, we investigated a possible role of SOCS-2 in the differentiation process of mesenchymal precursors. Stable transfection of SOCS-2 into C2C12 cells resulted in the acceleration of proliferation and survival, and inhibition of spontaneous myotube formation. In addition, SOCS-2 potentiated bone morphogenic protein (BMP)-induced transdifferentiation of C2C12 cells into osteoblast phenotypes. These effects of SOCS-2 on C2C12 cells differed strikingly from that of SOCS-1, another member of SOCS family, and its mechanisms were evaluated. SOCS-2 did not alter BMP-induced phosphorylation and nuclear accumulation of Smad1, nor the expression of inhibitory-Smads mRNA. However, SOCS-2 enhanced BMP-induced transcriptional activation of the Smad-responsive reporter gene, suggesting that the action of SOCS-2 is exerted at the transcriptional level. Interestingly, SOCS-2 overexpression in C2C12 cells increased the endogenous JunB protein, one of the key transcriptional factors in the control of BMP/Smad signaling responsiveness. In addition, the proteasome inhibitor enhanced JunB protein expression in C2C12 cells. Moreover, we found that SOCS-2 reduced JunB ubiquitination in COS-7 cells. Although SOCS-2 is a modulator of growth hormone (GH) signaling, the upregulation of JunB by SOCS-2 did not require GH signaling. Taken together, these results suggest that SOCS-2 positively regulates endogenous JunB protein expression in C2C12 cells through inhibition of JunB destabilization by the ubiquitin-proteasome pathway, and thereby regulates the cell fate of mesenchymal precursors.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002522:Chlorocebus aethiops; D015870:Gene Expression / Q000235:genetics; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D007976:Leupeptins; D017570:MyoD Protein; D018008:Myogenin; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D051785:Smad Proteins; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D015675:Osteocalcin; D000469:Alkaline Phosphatase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde