of work: Progression of eukaryotic cells through the various phases of the cell cycle is controlled to a large extent by the cyclin-dependent kinase system. The critical catalytic activity of the kinases is regulated by a complex system involving coupling with a cyclin partner, phosphorylation status of certain amino acid residues within the catalytic unit and also by a family of low molecular weight inhibitors.We have shown that one of these inhibitors,p27Kip1,is transcriptionally downregulated in the presence of IL-2. T-cells derived from aging mice have been shown to produce low levels of IL-2 which may account for the persistent levels of p27Kip1 observed in activated cells derived from old mice where a significant portion of cells fail to traverse G1. Among the T-cell subsets,high levels of p27Kip1 are present in the CD8+ cells as compared to similar cells derived from young mice. Methylation sensitive restriction enzymes show different patterns of promoter methylation in T-cells and T-cell subsets derived from young and old mice. More definitive studies are required using PCR based sequencing of the suspected regions to determine if differential methylation of the p27Kip1 promoter accounts for the age associated changes observed in p27Kip1 levels. Progression of activated T-cells through the G1 phase is dependent on the kinase activity of cdk2 which is efficiently inhibited by p27Kip1. Mice lacking functional p27Kip1 as a result of genetic manipulation (p27Kip1 knockout mice) have been recently made available to investigate the mechanism(s) involved in regulating the G1 phase of the cell cycle. The spleens of knockout mice contained 3-5 times the number of G0 T-cells as normal mice. In addition,unlike normal mice,the cdk2 catalytic activity was detected in resting T-cells and remained elevated during the entire G1 phase of the cell cycle. Following polyclonal activation, there was no detectable differences in the length of any of the cell phases and the distribution of cells among the cell phases was identical. Various cellular treatments that inhibit progression of T-cells through the G1 phase (which correlated with an increase in the level of p27Kip1) were equally effective in inhibiting the progress of T-cells derived from the knockout mice through the G1 phase. The lack of a functional p27Kip1 inhibitor in vivo has to date had no significant effect on the progression of activated T-cells through the cell cycle.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Intramural Research (Z01)
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National Institute on Aging
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