title: Differential effects of STAT proteins on growth hormone-mediated IGF-I gene expression.
abstract: Growth hormone (GH) plays a key role regulating somatic growth and in controlling metabolism and other physiological processes in humans and other animal species. GH acts by binding to the extracellular part of its transmembrane receptor, leading to induction of multiple intracellular signal transduction pathways that culminate in changes in gene and protein expression. A key agent in GH-stimulated growth is the latent transcription factor signal transducer and activator of transcription (STAT) 5B, one of four STAT proteins induced by the GH receptor in cultured cells and in vivo. As shown by genetic and biochemical studies, GH-activated STAT5B promotes transcription of the gene encoding the critical growth peptide, insulin-like growth factor-I (IGF-I), and natural null mutations of STAT5B in humans lead to growth failure accompanied by diminished IGF-I expression. Here we have examined the possibility that other GH-activated STATs can enhance IGF-I gene transcription, and thus potentially contribute to GH-regulated somatic growth. We find that human STAT5A is nearly identical to STAT5B in its biochemical and functional responses to GH but that STAT1 and STAT3 show a weaker profile of in vitro binding to STAT DNA elements from the IGF-I gene than STAT5B, and are less potent inducers of gene transcription through these elements. Taken together, our results offer a molecular explanation for why STAT5B is a key in vivo mediator of GH-activated IGF-I gene transcription and thus of GH-regulated somatic growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon.
authors.forename: Ben
authors.initials: B
authors.lastname: Varco-Merth
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon rotweinp@ohsu.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Rotwein
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002467:Cell Nucleus; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: gene transcription; insulin-like growth factor-I; signal transducer and activator of transcription; signal transduction