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Beta-catenin is a transcriptional coactivator that promotes cell proliferation by induction of genes such as cyclin D1, c-myc, and others. Enhanced b-catenin signaling was observed in many cancer cells and in vascular smooth muscle cells (VSMC) during restenosis. The canonical mechanism of regulation of b-catenin involves its phosphorylation by glycogen synthase kinase 3 (GSK3) that targets b-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote b-catenin signaling through inhibition of GSK3, resulting in reduced b-catenin phosphorylation, its stabilization, and subsequent accumulation in the nucleus, where it stimulates gene transcription. In the present study, we investigated the mechanism of VSMC proliferation induced by extracellular ATP (a VSMC mitogen relevant to the pathogenesis of atherosclerosis and restenosis). We found that (1) ATP potently induces the …