Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2

K. C. Leung*, N. Doyle, M. Ballesteros, K. Sjogren, C. K. W. Watts, T. H. Low, G. M. Leong, R. J. M. Ross, K. K. Y. Ho

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

174 Citations (Scopus)

Abstract

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-@a expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the β-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17β-estradiol (E2) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E2 was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E2 suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E2 inhibition. E2 increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E2 was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GH/JAK/STAT pathway, in which SOCS-2 plays a central mechanistic role.

Original languageEnglish
Pages (from-to)1016-1021
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number3
DOIs
Publication statusPublished - 4 Feb 2003
Externally publishedYes

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