LACK OF CYCLIN D-CDK COMPLEXES IN RB-NEGATIVE CELLS CORRELATES WITH HIGH-LEVELS OF P16(INK4 MTS1) TUMOR-SUPPRESSOR GENE-PRODUCT/

D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, regulate events in the G(1) phase of the cell cycle and may c ontribute to the phosphorylation of the retinoblastoma gene product (R b). However, in cells in which the function of Rb has been compromised , either by naturally arising mutations or through binding to proteins encoded by DNA tumour viruses, Cdk4 and Cdk6 are not associated with D cyclins. Instead, both kinases form binary complexes with a stable 1 6 kDa protein (p16) encoded by the putative tumour suppressor gene INK 4/ MTS1 on human chromosome 9p21. Here we show an inverse correlation between Rb status and the expression of p16. Since Rb-negative cells e xpress high levels of p16, we suggest that in these cells p16 competes with D cyclins for binding to Cdk4 and Cdk6 and prevents formation of active complexes. In line with these predictions, DNA tumour virus on coproteins do not disrupt cyclin D1-Cdk4 complexes in cells lacking p1 6.