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. Experiments 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 antibody, cell survival was sharply reduced. In CHO cells stably expressing either the wild-type (wtGHR) or a truncated form (delta454GHR) of the GH receptor in which GH induces a sustained activation of the receptor-associated tyrosine kinase JAK2, we found that GH stimulation inhibited programmed cell 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 mutated GHR unable to transduce the signal (4P/AGHR). We also showed that the inhibitory action of GH on apoptosis is probably mediated via stimulation of the serine-threonine kinase Akt, as 1) GH treatment induces a prompt phosphorylation of Akt; and 2) GH effects on cell survival are abolished by transfection of an Akt mutant that exhibits dominant negative function. Experiments with pharmacological inhibitors demonstrated that GH-induced Akt phosphorylation is dependent on phosphoinositide 3-kinase activation. In contrast, we found no changes in Bcl-2 levels secondary to GHR activation.
Costoya
J A
JA
Departamento de Fisioloxía, Facultade de Medicina, Universidade de Santiago de Compostela, Spain.
Finidori
J
J
Moutoussamy
S
S
Seãris
R
R
Devesa
J
J
Arce
V M
VM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004789:Enzyme Activation; D015870:Gene Expression; D018922:HL-60 Cells; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011986:Receptors, Somatotropin / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt