Age-associated decline in cdk1 activity delays cell cycle progression of human T lymphocytes.
Despite the repeatedly observed impaired proliferative response of T lymphocytes from aged donors, the precise molecular basis underlying such a defect is still poorly understood. The aim of this study was to determine whether cyclin-dependent kinase 1 (cdk1), a serine-threonine kinase required for entry into mitosis, is implicated in this age-associated dysregulation of the cell cycle. T lymphocytes derived from young and elderly donors were blocked in S phase by hydroxyurea after a 48-h activation by anti-CD3 Abs. Under these experimental conditions, only the cells that were already located beyond the S phase were able to complete the cell cycle, decreasing their DNA content from 4n to 2n chromosomes. Using this procedure, a delay in the accomplishment of mitosis could be observed in cells from elderly individuals, as evidenced by propidium iodide staining. In this age group, only a minimal cdk1 activity could be immunoprecipitated from cells sorted in G2/M after nocodazole block. The decrease in cdk1 activity observed in T lymphocytes from aged donors could be accounted for by at least three mechanisms: 1) a failure of these cells to express a sufficient amount of cdk1, 2) a reduced level of the associated cyclin B1, and 3) an incomplete dephosphorylation of the kinase on tyrosine. This low cdk1 activity is likely to postpone the progression through the G2/M transition and participates in the dysfunction of the cell cycle during the process of aging.
Quadri
R A
RA
Department of Geriatrics, University of Geneva, Switzerland.
Arbogast
A
A
Phelouzat
M A
MA
Boutet
S
S
Plastre
O
O
Proust
J J
JJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000378:metabolism*; D002453:Cell Cycle / Q000276:immunology*; D019926:Cyclin B / Q000096:biosynthesis; D056744:Cyclin B1; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D016195:G2 Phase / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D046911:Macromolecular Substances; D008938:Mitosis / Q000276:immunology; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology
D000911:Antibodies, Monoclonal; C534699:CCNB1 protein, human; D017252:CD3 Complex; D019926:Cyclin B; D056744:Cyclin B1; D007376:Interleukin-2; D046911:Macromolecular Substances; D016203:CDC2 Protein Kinase