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Growth Hormone Prevents Apoptosis through Activation of Nuclear Factor-B in Interleukin-3-Dependent Ba/F3 Cell Line

INSERM Unité 344, Endocrinologie Moléculaire (S.J., M.C.P-V., E.B.) Faculté de Médecine Necker Paris Cedex 15, France 75730
Department of Biochemistry (G.E.S.) Boston University School of Medicine Boston, Massachusetts 02118

The pro-B Ba/F3 cell line requires interleukin-3 and serum for growth, and their removal results in cell apoptosis. Ba/F3 cells transfected with the GH receptor (GHR) cDNA become able to proliferate in response to GH. To investigate the role of GH in the control of apoptosis, Ba/F3 cells expressing either the wild-type rat GHR (Ba/F3 GHR) or a mutated rat GHR (Ba/F3 ILV/T) were used. We show that Ba/F3 GHR cells, but not parental Ba/F3 or Ba/F3 ILV/T cells, were able to survive in the absence of growth factor. Furthermore, an autocrine/paracrine mode of GH action was suggested by the demonstration that Ba/F3 cells produce GH, and that addition of GH antagonists (B2036 and G120K) promotes apoptosis of Ba/F3 GHR cells. Consistent with survival, the levels of both antiapoptotic proteins Bcl-2 and Bag-1 were maintained in Ba/F3 GHR cells, but not in parental Ba/F3 cells upon growth factor deprivation. Constitutive activation of the transcription factor nuclear factor-B (NF-B), which has been shown to promote cell survival, was sustained in Ba/F3 GHR cells, whereas no NF-B activation was detected in parental Ba/F3 cells in the absence of growth factor. Furthermore, addition of GH induced NF-B DNA binding activity in Ba/F3 GHR cells. Overexpression of the mutated IB (A32/36) protein, known to inhibit NF-B activity, resulted in death of growth factor-deprived Ba/F3 GHR cells, and addition of GH was no longer able to rescue these cells from apoptosis. Together, our results provide evidence for a new GH-mediated pathway that initiates a survival signal through activation of the transcription factor NF-B and sustained levels of the antiapoptotic proteins Bcl-2 and Bag-1.

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