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

Leung, K. C., Doyle, N., Ballesteros, M., Sjogren, K., Watts, C. K. W., Low, T. H., Leong, G. M., Ross, R. J. M. and Ho, K. K. Y. (2003) Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proceedings of The National Academy of Sciences of The United States of America, 100 3: 1016-1021.


Author(s) Leung, K. C.
Doyle, N.
Ballesteros, M.
Sjogren, K.
Watts, C. K. W.
Low, T. H.
Leong, G. M.
Ross, R. J. M.
Ho, K. K. Y.
Title Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2
Journal name Proceedings of The National Academy of Sciences of The United States of America
Publication date 2003
Sub-type Article
Volume number 100
Issue number 3
ISSN 0027-8424
Start page 1016
End page 1021
Total pages 6
Place of publication Washington
Publisher Natl Acad Sciences
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 beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E-2) 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 E-2 was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E-2 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 E-2 inhibition. E-2 increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E-2 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.
Keyword(s) Multidisciplinary Sciences
Growth-hormone Receptor
Messenger-ribonucleic-acid
Factor-i Receptor
Replacement Therapy
Dna-binding
Postmenopausal Women
Stat Proteins
Cross-talk
Expression
Superfamily
 
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