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Endothelin-1 stimulates transcription of cyclin D1 and Skp2 through activation of Stat3 in cultured rat astrocytes

Activation of Stat3, a member of the Stat family of transcription factors, plays a pivotal role in induction of reactive astrocytes and glial scar formation. Endothelin-1 (ET-1) increases in brain disorders and promotes astrocytic proliferation through ET B receptors. In this study, to clarify mechanisms underlying astrocytic proliferation, the effects of ET-1 on Stat3 were examined in rat cultured astrocytes. Treatment with ET-1 stimulated Ser727 phosphorylation of Stat3 in cultured astrocytes, although Tyr705 phosphorylation was not affected. ET-1 stimulated the binding of Stat3 protein to its consensus DNA fragments. ET-induced BrdU incorporation was reduced by Stat3 inhibitors and Stat3 siRNA. ET-1 increased the expression of cyclin D1 and Skp2 in cultured astrocytes. The effects of ET-1 on cyclin D1 and Skp2 expression were reduced by stattic, 5,15-DPP and Stat3 siRNA. ChIP-PCR analysis showed that ET-1 promoted the binding of Stat3 to 5'-flanking regions of rat cyclin D1 and Skp2 genes. These results suggest that cyclin D1 and Skp2 expression through Stat3-mediated mechanisms underlies ET-induced astrocytic proliferation.