Activation of growth hormone receptor delivers an antiapoptotic signal: Evidence for a role of Akt in this pathway

A signaling pathway was delineated by which GH promotes cell survival. Expe riments were performed in human leukemic cells (HL-60) and Chinese hamster ovary (CHO) cells. In HL-60 cells, GH treatment reduced starvation-induced cell death. In contrast, when HL-60 cells were treated with an anti-GH anti body, cell survival was sharply reduced. In CHO cells stably expressing eit her the wild-type (wtGHR) or a truncated form (Delta 454GHR) of the GH rece ptor in which GH induces a sustained activation of the receptor-associated tyrosine kinase JAK2, we found that GH stimulation inhibited programmed cel l death induced by withdrawal of survival factors. This effect was enhanced in cells expressing the truncated form. In contrast,GH did not affect cell survival in CHO cells transfected with either the empty vector or a mutate d GHR unable to transduce the signal (4P/AGHR). We also showed that the inh ibitory action of GK on apoptosis is probably mediated via stimulation of t he serine-threonine kinase Akt, as 1) GH treatment induces a prompt phospho rylation of Akt; and 2) GH effects on cell survival are abolished by transf ection of an Akt mutant that exhibits dominant negative function. Experimen ts with pharmacological inhibitors demonstrated that GH-induced Akt phospho rylation is dependent on phosphoinositide 3-kinase activation. In contrast, we found no changes in Bcl-2 levels secondary to GHR activation.