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Up-Regulation of Insulin-Like Growth Factor Binding Protein-5 Is Independent of Muscle Cell Differentiation, Sensitive to Rapamycin, But Insensitive to Wortmannin and LY294002¹

Institut National de la Santé et de la Recherche Médicale (S.R., C.D.), U.142, Hôpital Saint Antoine, 75571 Paris Cedex 12, France; and Laboratoire de développement cellulaire (D.M., C.P.), Unité de Recherche Associée au Centre National de Recherche Scientifique 1947, Institut Pasteur, 75724 Paris Cedex 15, France

Address all correspondence and requests for reprints to: Dr. Catherine Dubois, Institut National de la Santé et de la Recherche Médicale, U.142, Hôpital Saint Antoine, 75571 Paris Cedex 12, France. E-mail: dubois{at}st-antoine.inserm.fr Or, Dr.

Skeletal myoblast differentiation is stimulated by insulin-like growth factors (IGFs). The autocrine action of IGFs is mediated through the type-1 IGF receptor (IGFR-1) and modulated by IGF binding proteins (IGFBPs) secreted by the cells. The mouse C2 myoblast cell line stably transfected with a vector producing IGF-II antisense RNA was used to show that specific IGFBP expression changes with the state of the cells: high levels of IGFBP-2 messenger RNA (mRNA) were found only in proliferating myoblasts, whereas IGFBP-3 mRNA was induced in quiescent cells. Secretion of IGFBP5 was strongly stimulated during differentiation. Insulin and IGF dose-response experiments showed that up-regulation of IGFBP-5 resulted from IGFR-1 activation. Drugs interfering with IGFR-1 signaling and inhibiting myoblast differentiation had different effects on IGFBP-5 up-regulation. Two phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, wortmaninn and LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], failed to alter IGFBP-5 up-regulation, which persisted in the absence of differentiation. Rapamycin which indirectly prevents activation of the p70 ribosomal protein-S6 kinase (p70^S6k), suppressed IGFBP-5 induction. Because the PI3-kinase inhibitors block p70^S6k, neither kinase would be required for IGFR-1-dependent IGFBP-5 induction. In C2 anti-IGF-II myoblasts, IGFBP-5 induction is therefore rapamycin-sensitive and independent of differentiation.

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