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

• 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-alpha 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 GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

Blotting

Western

Caseins

metabolism

Cell Line

DNA-Binding Proteins

metabolism

Dactinomycin

pharmacology

Dose-Response Relationship

Drug

Estradiol

metabolism

Estrogens

metabolism

Fibroblasts

metabolism

Genes

Reporter

Human Growth Hormone

metabolism

Humans

Interleukin-6

metabolism

Janus Kinase 2

Milk Proteins

Phosphorylation

Plasmids

metabolism

Precipitin Tests

Protein-Tyrosine Kinases

metabolism

Proteins

metabolism

Proto-Oncogene Proteins

Recombinant Proteins

metabolism

Repressor Proteins

STAT3 Transcription Factor

STAT5 Transcription Factor

Signal Transduction

Suppressor of Cytokine Signaling Proteins

Trans-Activators

metabolism

Transcription Factors

Transcription

Genetic

Vanadates

pharmacology

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