title: CREB participates in the IGF-I-stimulation cyclin D1 transcription.
abstract: IGF-I stimulates proliferation and cell cycle progression in progenitor cells of a number of neural cell types, including neuronal and glial progenitors. The precise mechanisms of this regulation, however, have not been fully defined. To elucidate the mechanism of IGF-I actions on neural cell proliferation, we utilized a rat oligodendroglial cell line (OL-1) and primary oligodendrocyte precursors (OPC) and studied IGF-I regulation of cyclin D1 expression and its promoter activity, because cyclin D1 is critical to the promotion of cell proliferation and cell cycle progression. Transient transfection of a reporter driven by the rat cyclin D1 promoter showed that IGF-I stimulates cyclin D1 promoter activity. Furthermore, 5'-end deletions and mutation analysis of this promoter revealed that a cAMP response element (CRE) within -174 base pair (bp) upstream of the transcription start site is crucial to the IGF-induced increase in cyclin D1 transcription. Consistently, Western immunoblot analysis demonstrated that IGF-I induced CREB (CRE binding protein) phosphorylation, while ablation of CREB expression with small interfering RNAs (siRNA) blocked IGF-I actions on cyclin D1 mRNA expression and cell proliferation. Additionally, IGF-I-stimulated CREB phosphorylation was blunted by the MAP kinase inhibitor, PD98059, but not by the PI3 kinase inhibitor, wortmannin. ChIP assays revealed that IGF-1 increased the association of CREB with the cyclin D1 promoter. Taken together, our data indicate that IGF-I upregulates cyclin D1 transcription partially by inducing CREB phosphorylation through the ERK-MAP kinase pathway, and thus increasing its recruitment to the cyclin D1 promoter. These results provide an important mechanism of IGF-I-induced glial cell growth and proliferation. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 559-570, 2013.
authors: Department of Pediatrics, Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. yyan@cmh.edu
authors: Yun
authors: Y
authors: Yan
authors: Xiaoyu
authors: X
authors: Li
authors: Karen
authors: K
authors: Kover
authors: Mark
authors: M
authors: Clements
authors: Ping
authors: P
authors: Ye
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: CREB; Cyclin D1; IGF-I; oligodendrocytes; signaling transduction