Intracellular signaling by growth hormone variant (GH-V)

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Abstract

Placental growth hormone, or growth hormone variant (GH-V), is a member of the growth hormone gene family. Its physiologic role during pregnancy remains undefined. Although extensive work has been done characterizing the signaling pathways activated by hGH, the signaling pathways which are activated by GH-V have not been characterized. We investigated cellular signaling by GH-V in model systems in which signaling by hGH has been well characterized. GH-V activates the STAT5b transcription factor in the IM-9 human lymphocyte and 3T3-F442A preadipocyte cell lines, and in primary porcine smooth muscle cells, which all homologously express GH receptors. In contrast, hCS does not activate signaling in these GH receptor-expressing cells. Like hGH, signaling by GH-V is inhibited by the GH antagonist (G120K). These results provide preliminary evidence that GH-V plays a major role in affecting target cells expressing the GH receptor, thus potentially exerting significant GH-like effects on maternal physiology during pregnancy.

Section snippets

INTRODUCTION

The human GH gene cluster contains five structural genes:1 hGH (pituitary GH gene), expressed by somatotropes in the anterior pituitary, hCS-A and hCS-B, the two chorionic somatomammotropin genes expressed in the placenta (also known as human placental lactogen, hPL), and hCS-L, chorionic somatomammotropin-like gene. In addition, Seeburg reported the existence of a growth hormone-variant gene or GH-V, in 1982.2 Subsequent gene expression was localized to the villous syncytiotrophoblasts.[3], [4]

Reagents

Recombinant human growth hormone (rhGH) and recombinant human prolactin (rhPrl) were from Genentech (San Francisco, CA). The hCS was purchased from Sigma (St. Louis, MO). The enhanced chemiluminescence kit (ECL) was purchased from Amersham (Arlington Heights, IL). Anti-phosphotyrosine antibody was a monoclonal (py99) from Santa Cruz Biotechnology (Santa Cruz, CA). Polyclonal STAT5a and STAT5b specific antibodies were developed in our laboratory.20 Peptides used to generate the antibodies

RESULTS

Using cell model systems which are known targets of pituitary growth hormone (rhGH or GH-N) action,[24], [25], [26] we have investigated the ability of placental growth hormone or growth hormone-variant (GH-V) to activate similar signaling. Importantly, we have also tested the effect of human chorionic somatomammotropin (hCS, or human placental lactogen/hPL) in these model systems in order to determine which effects are specific to GH-V. These studies are aimed at not only understanding the

DISCUSSION

We have shown that human placental growth hormone variant (GH-V) activates the signal transducer and activator of transcription, STAT5b, in a manner similar to that seen with human pituitary growth hormone (GH-N). GH-N and GH-V both activate STAT5b in GH receptor-expressing cell models, while the related placental hormone, human chorionic somatomammotropin (hCS), does not. However, in the Nb2 cell model which expresses Prl receptors, but not GH receptors, GH-N, GH-V, hCS, and Prl all activate

Acknowledgements

We thank Dr. Nancy Cooke and Dr. Stephen Liebhaber for the C127 cells, Dr. Arthur Buckley for the Nb2 cells, and Dr. Gary Owens for the smooth muscle cells. In addition, we thank Dr. Christian Strasburger and Dr. Zida Wu for their measurements of recombinant GH-V. We are especially grateful for helpful conversations and critical reading of the manuscript by Dr. Eugene Barrett.

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    Supported in part by NIH Grants R29-DK48481 and 3M01-RR00847-22S1.

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