DEREGULATION OF CYCLIN-D1 AND CYCLIN-E AND SUPPRESSION OF CDK2 AND CDK4 IN SENESCENT HUMAN FIBROBLASTS

The state of cellular senescence is characterised by an irreversible a rrest in the G1 phase of the cell cycle. It has previously been shown that three cell cycle genes, cyclin A, cyclin B and cdc2, are not expr essed in senescent human fibroblasts. All three gene products have fun ctions after S-phase entry, so that their suppression cannot explain t he irreversible G1 arrest. Here, we report that the abundance of trans cripts from two other cell cycle genes, cdk2 and cdk4, thought to act during G1-->S progression, is significantly diminished in senescent ce lls of the diploid human fibroblast line WI-38. Surprisingly, two othe r cyclins, D1 and E, behave in a completely different way, in that the ir expression is elevated in senescent cells, especially under conditi ons of serum starvation. Both the synthesis and the steady-state level of cyclin D1 protein were also found to be markedly higher in senesce nt cells (3- to 6-fold). Cyclins D1 and E are thus the first genes sho wn to be overexpressed or deregulated in senescent cells. It is tempti ng to speculate that this deregulation may be due to the absence, in s enescent cells, of a regulatory loop that would normally control their expression. This is supported by our finding that cyclin E-associated kinase activity in senescent cells is reduced approx. 14-fold. Our da ta also suggest that the deregulated expression of cyclin DI and E is not sufficient to drive senescent cells into DNA replication.