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FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts
Author(s) -
Bois Philippe R.J.,
Grosveld Gerard C.
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg116
Subject(s) - phosphorylation , microbiology and biotechnology , biology , foxo1 , transcription factor , cell fusion , fusion protein , kinase , cell cycle , protein kinase b , apoptosis , myocyte , cell culture , genetics , gene , recombinant dna
Activation of the transcription factor FKHR ( F or k head in h uman r habdomyosarcoma, FOXO1a) in various established cell lines induces cell cycle arrest followed by apoptosis. These effects are inhibited through activation of the phosphatidylinositol 3‐kinase/Akt pathway, resulting in FKHR phosphorylation and its export from the nucleus, thus blocking its pro‐apoptotic activity. Here we report that FKHR regulates fusion of differentiating primary myoblasts. We demonstrate that FKHR is localized in the cytoplasm of proliferating myoblasts, yet translocates to the nucleus by a phosphorylation‐independent pathway following serum starvation, a condition that induces myoblast differentiation. FKHR phosphorylation during terminal differentiation appears to downregulate its fusion activity, as a dominant‐active non‐phosphorylatable FKHR mutant dramatically augments the rate and extent of myotube fusion. However, this FKHR mutant exerts its effects only after other events initiated the differentiation pro cess. Conversely, enforced expression of a dominant‐negative FKHR mutant blocks myotube formation whereas wild‐type FKHR has no effect. We conclude that in addition to the role of FoxO proteins in regulating cell cycle progress and apoptosis, FKHR controls the rate of myotube fusion during myogenic differentiation.