Cyclin-dependent kinase 6 is the principal target of p27/Kip1 regulation of the G(1)-phase traverse in 1,25-dihydroxyvitamin D-3-treated HL60 cells

Control of cell proliferation remains of intense interest in cancer research. In the 1,25-dihydroxyvitamin D-3 HL60 cell system, G(1) arrest has been shown to be mediated by elevated levels of p27/Kip1 protein. We show here that the main target of the elevated p27/Kip1 in this system is cyclin-dependent kinase (Cdk) 6. The activity of Cdk2 is also down-regulated, and this is associated with altered and reduced levels of cyclin E in the kinase complex. Paradoxically, the kinase activity of Cdk4 is elevated, in spite of an almost complete G(1) block. These data show that the functions of Cdk4 and Cdk6 are not redundant and that Cdk6 and Cdk2 activities are regulated by 1,25-dihydroxyvitamin D-3.