D. Parry et al., LACK OF CYCLIN D-CDK COMPLEXES IN RB-NEGATIVE CELLS CORRELATES WITH HIGH-LEVELS OF P16(INK4 MTS1) TUMOR-SUPPRESSOR GENE-PRODUCT/, EMBO journal, 14(3), 1995, pp. 503-511
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.