Cyclin-dependent kinase 5 activity enhances monocytic phenotype and cell cycle traverse in 1,25-dihydroxyvitamin...

The function of most cyclin-dependent kinases (Cdks) is to facilitate progression through the checkpoints of the cell cycle, but Cdk5 is known to be involved in differentiation of CNS, muscle, and lens cells, though not in the cell cycle traverse. Here we show an additional role for Cdk5, an enhancement of monocytic differentiation with abrogation of the G1 checkpoint. Human leukemia HL60 cells exposed to 1alpha,25-dihydroxyvitamin D3 (1,25D3) displayed monocytic phenotype and increased Cdk5 kinase activity. An analog of 1,25D3 which does not induce differentiation failed to upregulate Cdk5, and 1,25D3-resistant cells had reduced Cdk5 activity. Active or inactive Cdk5 was associated with cyclin D1, but only active Cdk5 exhibited threonine phosphorylation. Inhibition of Cdk5 expression by an antisense construct reduced the intensity of 1, 25D3-induced expression of CD14, a marker of monocytes, and increased the 1,25D3-induced G1 block. These findings demonstrate a novel aspect of Cdk5 activity-facilitation of the G1- to S-phase transition in cells which are approaching replicative quiescence and a concomitant enhancement of monocytic differentiation.