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Growth Hormone Exerts Antiapoptotic and Proliferative Effects through Two Different Pathways Involving Nuclear Factor-B and Phosphatidylinositol 3-Kinase¹

INSERM, U-344, Endocrinologie Moléculaire, Faculté de Médecine Necker (S.J., P.A.K., M.C.P.V., E.B.), 75730 Paris, France; and Department of Biochemistry, Boston University School of Medicine (G.E.S.), Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dr. Marie-Catherine Postel-Vinay, INSERM, U-344, Faculté Necker-Enfants Malades, 156 rue de Vaugirard, 75015 Paris, France. E-mail: postel-vinay{at}necker.fr

Dependence of murine pro-B Ba/F3 cells on interleukin-3 can be substituted by GH when cells are stably transfected with the GH receptor (GHR) complementary DNA. Recently, we demonstrated that Ba/F3 cells produce GH, which is responsible for the survival of cells expressing the GHR. This GH effect involves the activation of nuclear factor-B (NF-B). Here, we examined the signaling pathways mediating proliferation of growth factor-deprived Ba/F3 GHR cells. Exogenous GH stimulation of Ba/F3 GHR cells induced cyclins E and A and the cyclin-dependent kinase inhibitor p21^waf1/cip1 and repressed cyclin-dependent kinase inhibitor p27^kip1. The presence of the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor Ly 294002 abolished proliferation induced by GH, arresting Ba/F3 GHR cells at the G₁/S boundary, but did not promote apoptosis. Thus, the proliferative effect of GH is closely related to PI 3-kinase activation, whereas PI 3-kinase is not essential for GH-induced cell survival. Addition of Ly 294002 resulted in a moderate decrease in NF-B activation by GH, suggesting a possible link between PI 3-kinase and NF-B signaling by GH. Expression of c-myc was also induced by GH in Ba/F3 GHR cells, and inactivation of either PI 3-kinase or NF-B reduced this induction. Overexpression of the dominant negative repressor mutant c-Myc-RX resulted in an inhibition of the GH proliferative effect, suggesting the involvement of c-myc in GH-induced proliferation. Taken together, these results suggest that the effects of GH on cell survival and proliferation are mediated through two different signaling pathways, NF-B and PI 3-kinase, respectively; although cross-talk between them has not been excluded. NF-B, which has been shown to be responsible for the antiapoptotic effect of GH, could also participate in GH-induced proliferation, as c-myc expression is promoted by PI 3-kinase, in an NF-B-dependent and -independent manner.

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