ROLE OF SERINE THREONINE KINASE CASEIN KINASE-II IN VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION AND INHIBITION BY HEPARIN

The role of serine/threonine kinase casein kinase-II (CK-II) in vascular smooth muscle cell proliferation and inhibition by heparin was investigated. cDNAs for alpha and beta subunits of CK-II from rabbit vascular smooth muscle cells were cloned and sequenced. A strong evolutionary conservation was found at amino acid and nucleotide levels in CK-II from rabbit and human. Treatment of smooth muscle cells with a specific antisense oligonucleotide to CK-II blocked stimulation of DNA synthesis in response to PDGF. Addition of a known inhibitor of CK-II to cultures of smooth muscle cells also blocked DNA synthesis. Mitogenic stimulation of growth arrested quiescent cultures of smooth muscle cells with PDGF produced a 2-3-fold increase in CK-II activity. Heparin was a potent inhibitor of smooth muscle cell derived CK-II in vitro and attenuated the stimulation of CK-II activity in response to PDGF in intact cells. Intracellular localization studies showed that heparin and CK-II were localized in the nucleus. These results suggest a potential role of CK-II in signal transduction mediating smooth muscle cell growth. Modulation of CK-II activity by heparin and its co-localization in the nucleus suggest that heparin may effect CK-II activity in intact cells.