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.
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