title: Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation.
abstract: Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)-transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted inCry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement,Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 uponCrydeficiency correlates with reducedIgf-1mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone-induced, JAK2 kinase-mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles ofCry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced uponCrydeficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.
authors.affiliation: Center for Gene Regulation and Health and Disease and Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115.
authors.forename: Amol
authors.initials: A
authors.lastname: Chaudhari
authors.affiliation: Center for Gene Regulation and Health and Disease and Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115.
authors.forename: Richa
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Center for Gene Regulation and Health and Disease and Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115.
authors.forename: Sonal
authors.initials: S
authors.lastname: Patel
authors.affiliation: Center for Gene Regulation and Health and Disease and Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115.
authors.forename: Nikkhil
authors.initials: N
authors.lastname: Velingkaar
authors.affiliation: Center for Gene Regulation and Health and Disease and Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115 r.kondratov@csuohio.edu.
authors.forename: Roman
authors.initials: R
authors.lastname: Kondratov
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology; D056931:Cryptochromes / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004392:Dwarfism / Q000378:metabolism; D013006:Growth Hormone; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D056931:Cryptochromes; D004268:DNA-Binding Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2