Aging impairs induction of cyclin-dependent kinases and down-regulation of p27 in mouse CD4(+) cells.
To define the link between the early activation defects and the impaired proliferation response of cells from old mice, we characterized the influence of age on expression and activity of proteins that participate in cell-cycle regulation. We found that aging led to significant declines in the ability of mouse CD4(+) T cells to respond to CD3 and CD28 stimuli by induction of the cyclin-dependent kinases CDK2, CDK4, and CDK6, whether the defect was assessed by protein level or functional activity. Induction of CDK2 activity was also impaired in cells from old mice that were activated with PMA plus ionomycin, stimuli that bypass the TCR/CD3 complex, or by CD3/CD28 in the presence of IL-2, indicating that the age-related changes lie, at least in part, downstream of the enzymes activated by these stimuli. We also noted an impairment in the ability of CD4(+) cells from old mice to down-regulate the CDK inhibitor p27 after activation, but we found no change in induction of p21, an inhibitor of CDK that may also play other roles in cell-cycle control. Altered CDK activation is likely to mediate the age-related decline in T cell proliferation to polyclonal stimulation.
Tamir
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A
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Miller
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RA
D000375:Aging / Q000187:drug effects / Q000276:immunology*; D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007518:Isoantibodies / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D018106:CD28 Antigens; D017252:CD3 Complex; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D007518:Isoantibodies; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D013755:Tetradecanoylphorbol Acetate