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PMID:15749807

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Citation

Xu, J, Ji, S, Venable, DY, Franklin, JL and Messina, JL (2005) Prolonged insulin treatment inhibits GH signaling via STAT3 and STAT1. J. Endocrinol. 184:481-92

Abstract

Growth hormone (GH) and insulin are important regulators of cellular and whole body metabolism as well as somatic growth and body composition. Studies have indicated complex feedback effects of GH on insulin action and of insulin on GH signaling pathways. Previous studies in our laboratory have shown that GH induction of signal transducers and activators of transcription (STAT)5B tyrosine phosphorylation is inhibited by prolonged insulin treatment, probably via downregulation of GHR. Here, we find that in rat H4IIE hepatoma cells GH-induced tyrosine phosphorylation of two other STATs (STAT3 and STAT1) was also greatly reduced following prolonged insulin pretreatment compared with that induced by GH alone. In the present work, total STAT5B and STAT1 protein levels were not altered by prolonged insulin treatment. However, prolonged insulin treatment (16 h; 10 or 100 nM) resulted in a 30-40% reduction of total STAT3 protein, with little change at 0.1 and 1.0 nM insulin. Thus, there is a selective reduction of total STAT3 protein levels by insulin, but only at high concentration of insulin. Basal tyrosine phosphorylated (PY)-STAT3 was also significantly reduced by prolonged insulin treatment, and to a greater extent than total STAT3 protein levels. The inhibitory effect of insulin on total STAT3 protein and basal PY-STAT3 levels was dependent on activation of the MEK-ERK pathway, rather than the PI3K pathway. In contrast, the MEK-ERK pathway did not play a major role in insulin's inhibition of GH-induced PY-STAT3 and PY-STAT1. The present studies indicate that prolonged hyperinsulinemia, such as that found in some obese patients or patients with Type 2 diabetes mellitus, may have profound effects on GH signaling via STAT3 and STAT1.

Links

PubMed Online version:10.1677/joe.1.05977

Keywords

Animals; Cell Line, Tumor; DNA-Binding Proteins/analysis; DNA-Binding Proteins/metabolism; Dose-Response Relationship, Drug; Growth Hormone/metabolism; Growth Hormone/pharmacology; Insulin/metabolism; Insulin/pharmacology; Liver/metabolism; Luminescent Measurements; MAP Kinase Signaling System/drug effects; Phosphorylation; Rats; STAT1 Transcription Factor; STAT3 Transcription Factor; Time Factors; Trans-Activators/analysis; Trans-Activators/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:A0A0G2JX93

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:A0A0G2JX93

involved_in

GO:0043434: response to peptide hormone

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:F1M9D6

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:F1M9D6

involved_in

GO:0043434: response to peptide hormone

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q66HB2

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q66HB2

involved_in

GO:0043434: response to peptide hormone

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q6P6Q7

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q6P6Q7

involved_in

GO:0043434: response to peptide hormone

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0043434: response to peptide hormone

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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