title: Protein 4.1R Influences Myogenin Protein Stability and Skeletal Muscle Differentiation.
abstract: Protein 4.1R (4.1R) isoforms are expressed in both cardiac and skeletal muscle. 4.1R is a component of the contractile apparatus. It is also associated with dystrophin at the sarcolemma in skeletal myofibers. However, the expression and function of 4.1R during myogenesis have not been characterized. We now report that 4.1R expression increases during C2C12 myoblast differentiation into myotubes. Depletion of 4.1R impairs skeletal muscle differentiation and is accompanied by a decrease in the levels of myosin heavy and light chains and caveolin-3. Furthermore, the expression of myogenin at the protein, but not mRNA, level is drastically decreased in 4.1R knockdown myocytes. Similar results were obtained using MyoD-induced differentiation of 4.1R-/-mouse embryonic fibroblast cells. von Hippel-Lindau (VHL) protein is known to destabilize myogenin via the ubiquitin-proteasome pathway. We show that 4.1R associates with VHL and, when overexpressed, reverses myogenin ubiquitination and stability. This suggests that 4.1R may influence myogenesis by preventing VHL-mediated myogenin degradation. Together, our results define a novel biological function for 4.1R in muscle differentiation and provide a molecular mechanism by which 4.1R promotes myogenic differentiation.
authors: From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, shu-ching_huang@dfci.harvard.edu.|the Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.|the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Shu-Ching
authors: SC
authors: Huang
authors: From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
authors: Anyu
authors: A
authors: Zhou
authors: From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
authors: Dan T
authors: DT
authors: Nguyen
authors: From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
authors: Henry S
authors: HS
authors: Zhang
authors: From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.|the Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.|the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, and.|the Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115.
authors: Edward J
authors: EJ
authors: Benz
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; C000595222:protein 4.1R , mouse; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse
keywords: E3 ubiquitin ligase; myogenesis; myogenin; protein 4.1R; protein degradation; protein stability; ubiquitylation (ubiquitination); von Hippel Lindau