Growth hormone exerts antiapoptotic and proliferative effects through two different pathways involving nuclear factor-kappaB and phosphatidylinositol 3-kinase.
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-kappaB (NF-kappaB). 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 G(1)/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-kappaB activation by GH, suggesting a possible link between PI 3-kinase and NF-kappaB 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-kappaB 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-kappaB and PI 3-kinase, respectively; although cross-talk between them has not been excluded. NF-kappaB, 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-kappaB-dependent and -independent manner.
Jeay
S
S
INSERM, U-344, Endocrinologie Moléculaire, Faculté de Médecine Necker, 75730 Paris, France.
Sonenshein
G E
GE
Kelly
P A
PA
Postel-Vinay
M C
MC
Baixeras
E
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase; D017930:Genes, Reporter; D016259:Genes, myc; D013006:Growth Hormone / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011986:Receptors, Somatotropin / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016196:S Phase; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D002867:Chromones; D004791:Enzyme Inhibitors; D013006:Growth Hormone; D008156:Luciferases; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011986:Receptors, Somatotropin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one