THE REGULATION OF P27(KIP1) EXPRESSION FOLLOWING THE POLYCLONAL ACTIVATION OF MURINE G(0) T-CELLS

Polyclonal activation of murine G(0) T cells with immobilized anti-CD3 induces entry into the cell cycle as well as the subsequent cytokine- dependent proliferative response, G(0) T cells express high levels of p27(Kip1) protein and specific mRNA, which decline rapidly following a ctivation. The decline in the expression of p27(Kip1) and sequestering of the inhibitor), protein by cdk4 and cdk6 correlated with the incre ase in cdk2 kinase activity during the G(1) phase, Anti-CD3 activation of G(0) T cells in the presence of cyclosporin A or rapamycin inhibit ed the down-regulation of p27(Kip1), the cellular levels of the inhibi tor remained high, and the cells remained in the G(1) phase, PBu2 acti vation of G(0) T cells also did not result in the down-regulation of p 27(Kip1) and the cells remained in G(1). In each instance IL-2 restore d the down-regulation of p27(Kip1), resulting in a significant reducti on in the level of the inhibitor, and stimulated the cells to progress through the cell cycle, Jurkat cells transfected with the p27GL-988 p lasmid containing +l to -988 nt of the p27(Kip1) promoter region and s ubsequently exposed to rlL-2 resulted in a significant reduction in th e activity of the p27(Kip1) promoter, These findings suggest that in a ddition to providing the signals required for activated T cells to tra verse G(1)/S, IL-2 also influences the promoter function of p27(Kip1), which effectively induces transcriptional downregulation of the gene.