c-Myc regulates cyclin D-Cdk4 and-Cdk6 activity but affects cell cycle progression at multiple independent points

c-myc is a cellular proto-oncogene associated with a variety of human cance rs and is strongly implicated in the control of cellular proliferation, pro grammed cell death, and differentiation. We have previously reported the fi rst isolation of a c-myc-null cell line. Loss of c-Myc causes a profound gr owth defect manifested by the lengthening of both the G(1) and G(2) phases of the cell cycle. To gain a clearer understanding of the role of c-Myc in cellular proliferation, we have performed a comprehensive analysis of the c omponents that regulate cell cycle progression. The largest defect observed in c-myc(-/-) cells is a 12-fold reduction in the activity of cyclin D1-Cd k4 and -Cdk6 complexes during the G(0)-to-S transition. Downstream events, such as activation of cyclin E-Cdk2 and cyclin A-Cdk2 complexes, are delaye d and reduced in magnitude. However, it is clear that c-Myc affects the cel l cycle at multiple independent points, because restoration of the Cdk4 and -6 defect does not significantly increase growth rate. In exponentially cy cling cells the absence of c-Myc reduces coordinately the activities of all cyclin-cyclin-dependent kinase complexes. An analysis of cyclin-dependent kinase complex regulators revealed increased expression of p27(KIP1) and de creased expression of Cdk7 in c-myc(-/-) cells. We propose that c-Myc funct ions as a crucial link in the coordinate adjustment of growth rate to envir onmental conditions.