p16(INK4) mediates contact-inhibition of growth

Growth of non-transformed cells in vitro is regulated by density-dependent mechanisms via cell-cell contacts, leading to arrest in late G1-phase at co nfluency (contact-inhibition of growth). In the present study it is shown t hat this results from p16(INK4)-mediated dissociation of the complex cdk4-c yclin D1, which is responsible for the inactivation of the gate keeper of G 1-S transition, the retinoblastoma protein pRb, As consequence of the inact ivation of cdk4, downstream the activation of cdk2 and hyperphosphorylation and thus inactivation of pRb was impaired, Direct evidence for the central role of p16(INK4) in growth control comes from the observation that a comp etitive inhibitor of p16(INK4) repressed contact inhibition of growth, Thes e findings provide an explanation for the high incidence of mutation or los s of INK4 in human tumours.