title: Defining human insulin-like growth factor I gene regulation.
abstract: Growth hormone (GH) plays an essential role in controlling somatic growth and in regulating multiple physiological processes in humans and other species. Insulin-like growth factor I (IGF-I), a conserved, secreted 70-amino acid peptide, is a critical mediator of many of the biological effects of GH. Previous studies have demonstrated that GH rapidly and potently promotes IGF-I gene expression in rodents and in some other mammals through the transcription factor STAT5b, leading to accumulation of IGF-I mRNAs and production of IGF-I. Despite this progress, very little is known about how GH or other trophic factors control human IGF1 gene expression, in large part because of the absence of any cellular model systems that robustly express IGF-I. Here, we have addressed mechanisms of regulation of human IGF-I by GH after generating cells in which the IGF1 chromosomal locus has been incorporated into a mouse cell line. Using this model, we found that physiological levels of GH rapidly stimulate human IGF1 gene transcription and identify several potential transcriptional enhancers in chromatin that bind STAT5b in a GH-regulated way. Each of the putative enhancers also activates a human IGF1 gene promoter in reconstitution experiments in the presence of the GH receptor, STAT5b, and GH. Thus we have developed a novel experimental platform that now may be used to determine how human IGF1 gene expression is controlled under different physiological and pathological conditions.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Aditi
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Damir
authors.initials: D
authors.lastname: Alzhanov
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon; and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech Health University Health Sciences Center, El Paso, Texas peter.rotwein@ttuhsc.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Rotwein
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C583557:IGF1 protein, human; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: chromatin immunoprecipitation; epigenetics; gene transcription; growth hormone; insulin-like growth factor I; signal transducer and activator of transcription 5b