The Proliferative and Antiapoptotic Actions of Growth Hormone and Insulin-Like Growth Factor-1 Are Mediated through Distinct Signaling Pathways in the Pro-B Ba/F3 Cell Line.

Biological actions of GH can be direct or mediated through insulin-like growth factor I (IGF-I). In the interleukin-3 (IL-3)-dependent Ba/F3 cell line, IGF-I induces cell cycle entry and proliferation. Ba/F3 cells expressing the rat GH receptor (Ba/F3 GHR cells) have been shown to escape from apoptosis and to proliferate under GH stimulation. Using the Ba/F3 GHR cell model, we sought to dissect the signals elicited specifically by IGF-I or GH. In contrast to IGF-I or IL-3, GH is able to maintain cell cycle entry of Ba/F3 GHR cells cultured for 7 days in the absence of serum. The presence of IGF-I messenger RNA was not detected by RT-PCR, and by RIA, IGF-I was not found in culture medium of Ba/F3 GHR cells, unstimulated or stimulated by GH. Moreover, the addition of an anti-IGF-I antibody that blocks IGF-I effects suggests that the actions of GH are not mediated by IGF-I, but appear to be direct. GH or IGF-I stimulation increased expression of cyclins A and D(1) with comparable kinetics, whereas expression of p21(waf1/cip1) seemed delayed in IGF-I-stimulated cells compared with that in GH-stimulated cells. Contrary to GH or IL-3, IGF-I did not induce nuclear factor-kappaB DNA-binding activity in Ba/F3 cells. Inhibition of nuclear factor-kappaB through expression of the mutant IkappaBalpha (A32/36) abrogated the GH-mediated survival signal, but did not result in alterations of the cell cycle in Ba/F3 GHR cells treated with IGF-I. Phosphatidylinositol 3-kinase was required for both survival and proliferative responses to IGF-I. Transfection of a dominant negative form of AKT (AH-AKT) resulted in suppression of IGF-I-mediated cell survival, but not of the antiapoptotic effect of GH in Ba/F3 GHR cells. Thus, GH and IGF-I are able to promote cell survival and proliferation through independent and different pathways in Ba/F3 cells.

[1]  P. Kelly,et al.  Growth Hormone Exerts Antiapoptotic and Proliferative Effects through Two Different Pathways Involving Nuclear Factor-κB and Phosphatidylinositol 3-Kinase** This work was supported by INSERM, a grant from Association pour la Recherche sur le Cancer, and USPHS Grant CA-36355 from the NIH. , 2001, Endocrinology.

[2]  G. Sonenshein,et al.  Growth hormone prevents apoptosis through activation of nuclear factor-kappaB in interleukin-3-dependent Ba/F3 cell line. , 2000, Molecular endocrinology.

[3]  O. Delattre,et al.  Induction of p21Waf1/Cip1 by TNFα requires NF-κB activity and antagonizes apoptosis in Ewing tumor cells , 2000, Oncogene.

[4]  J. Costoya,et al.  Activation of Growth Hormone Receptor Delivers an Antiapoptotic Signal: Evidence for a Role of Akt in This Pathway1. , 1999, Endocrinology.

[5]  M. Welham,et al.  Dissociation of Apoptosis from Proliferation, Protein Kinase B Activation, and BAD Phosphorylation in Interleukin-3-mediated Phosphoinositide 3-Kinase Signaling* , 1999, The Journal of Biological Chemistry.

[6]  F. Lezoualc’h,et al.  Insulin-like Growth Factor-1-mediated Neuroprotection against Oxidative Stress Is Associated with Activation of Nuclear Factor κB* , 1999, The Journal of Biological Chemistry.

[7]  D. Kaplan,et al.  Akt-Dependent Potentiation of L Channels by Insulin-Like Growth Factor-1 Is Required for Neuronal Survival , 1999, The Journal of Neuroscience.

[8]  A. Atfi,et al.  Evidence for a role of NF-kappaB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor beta fusion protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. Kiess,et al.  Hormonal control of programmed cell death/apoptosis. , 1998, European journal of endocrinology.

[10]  S. Reed,et al.  Nuclear Accumulation of p21Cip1 at the Onset of Mitosis: a Role at the G2/M-Phase Transition , 1998, Molecular and Cellular Biology.

[11]  B. van der Burg,et al.  Mitogenic Signaling of Insulin-like Growth Factor I in MCF-7 Human Breast Cancer Cells Requires Phosphatidylinositol 3-Kinase and Is Independent of Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[12]  L. Peso,et al.  Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. , 1997, Science.

[13]  J Downward,et al.  PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. , 1997, Trends in biochemical sciences.

[14]  S. Doublier,et al.  Liver-Specific Expression of Human Insulin-Like Growth Factor Binding Protein-1 in Transgenic Mice: Repercussions on Reproduction, Ante- and Perinatal Mortality and Postnatal Growth. , 1997, Endocrinology.

[15]  M. Dardenne,et al.  Growth hormone stimulates the proliferation of activated mouse T lymphocytes. , 1997, Endocrinology.

[16]  P. Tsichlis,et al.  Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Klippel,et al.  Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt , 1997, Molecular and cellular biology.

[18]  Lewis C Cantley,et al.  PI3K: Downstream AKTion Blocks Apoptosis , 1997, Cell.

[19]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[20]  K. Endo,et al.  Regulation of Insulin-like Growth Factor-I Expression in Mouse Preadipocyte Ob1771 Cells (*) , 1996, The Journal of Biological Chemistry.

[21]  M. Karin,et al.  Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation , 1996, Molecular and cellular biology.

[22]  S. Arkins,et al.  Requirement for phosphatidylinositol 3'-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor. , 1996, Journal of immunology.

[23]  E. Hooghe-Peters,et al.  Prolactin, growth hormone, and insulin-like growth factor-I in the immune system. , 1996, Advances in immunology.

[24]  P. Kelly,et al.  The proline-rich region of the GH receptor is essential for JAK2 phosphorylation, activation of cell proliferation, and gene transcription. , 1995, Molecular endocrinology.

[25]  J. Cidlowski,et al.  Regulation of apoptosis by steroid hormones , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[26]  H. Pahl,et al.  Phosphorylation of human I kappa B‐alpha on serines 32 and 36 controls I kappa B‐alpha proteolysis and NF‐kappa B activation in response to diverse stimuli. , 1995, The EMBO journal.

[27]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[28]  D. Morrison,et al.  AH/PH domain-mediated interaction between Akt molecules and its potential role in Akt regulation , 1995, Molecular and cellular biology.

[29]  James M. Roberts,et al.  lnterleukin-2-mediated elimination of the p27Kipl cyclin-dependent kinase inhibitor prevented by rapamycin , 1994, Nature.

[30]  G. Evan,et al.  c‐Myc‐induced apoptosis in fibroblasts is inhibited by specific cytokines. , 1994, The EMBO journal.

[31]  R. Aebersold,et al.  Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins. , 1994, The Journal of biological chemistry.

[32]  Janet Taylor,et al.  Comparison of Glucocorticoid-Induced Effects in Prolactin-Dependent and Autonomous Rat Nb2 Lymphoma Cells , 1993, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[33]  N. Bersch,et al.  Growth hormone mediates the growth of T-lymphoblast cell lines via locally generated insulin-like growth factor-I. , 1990, The Journal of clinical endocrinology and metabolism.

[34]  Y. Le Bouc,et al.  Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance. , 1989, The Journal of clinical endocrinology and metabolism.

[35]  L. Cavalli-Sforza,et al.  Insulin-like growth factor secretion by human B-lymphocytes: a comparison of cells from normal and pygmy subjects. , 1989, The Journal of clinical endocrinology and metabolism.