Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: a mechanism for repression of gene expression by growth hormone.
GH plays a central role in controlling somatic growth, tissue regeneration, and intermediary metabolism in most vertebrate species through mechanisms dependent on the regulation of gene expression. Recent studies using transcript profiling have identified large cohorts of genes whose expression is induced by GH. Other results have demonstrated that signal transducer and activator of transcription (Stat) 5b, a latent transcription factor activated by the GH receptor-associated protein kinase, Jak2, is a key agent in the GH-stimulated gene activation that leads to somatic growth. By contrast, little is known about the steps through which GH-initiated signaling pathways reduce gene expression. Here we show that Stat5b plays a critical role in the GH-regulated inhibition of IGF binding protein-1 gene transcription by impairing the actions of the FoxO1 transcription factor on the IGF binding protein-1 promoter. Additional observations using transcript profiling in the liver indicate that Stat5b may be a general mediator of GH-initiated gene repression. Our results provide a model for understanding how GH may simultaneously stimulate and inhibit the expression of different cohorts of genes via the same transcription factor, potentially explaining how GH action leads to integrated biological responses in the whole organism.
Ono
Mitsuru
M
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 Southwest Sam Jackson Road, Portland, Oregon 97239, USA.
Chia
Dennis J
DJ
Merino-Martinez
Roxana
R
Flores-Morales
Amilcar
A
Unterman
Terry G
TG
Rotwein
Peter
P
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation
D051858:Forkhead Transcription Factors; D050799:STAT5 Transcription Factor; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone