p27Kip1 regulates T cell proliferation.
Our studies addressed the mechanism by which serum acts in conjunction with T cell receptor (TCR) agonists to promote the proliferation of primary splenic T cells. When added to resting splenocytes, TCR agonists initiated G(0)/G(1) traverse and activated cyclin D3-cdk6 complexes in a serum-independent manner. On the other hand, both TCR agonists and 10% serum were required for the activation of cyclin E-cdk2 and cyclin A-cdk2 complexes and the entry of cells into S phase. Serum facilitated cdk2 activation by maximizing the extent and extending the duration of the TCR-initiated down-regulation of the cdk2 inhibitor, p27(Kip1). Although p27(Kip1) levels were reduced (albeit submaximally) in cells stimulated in serum-deficient medium, nearly all of the cdk2 complexes in these cells contained p27(Kip1). In contrast, in cells receiving TCR agonist and 10% serum, little if any p27(Kip1) was present in cyclin-cdk2 complexes. Unlike wild-type splenocytes, p27(Kip1)-null splenocytes did not require serum for cdk2 activation or S phase entry whereas loss of the related cdk2 inhibitor, p21(Cip1), did not override the serum dependence of these responses. We also found that cdk2 activation was both necessary and sufficient for maximal expression of cdk2 protein. These studies provide a mechanistic basis for the serum dependence of T cell mitogenesis.
Mohapatra
S
S
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, Department of Biochemistry, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
Agrawal
D
D
Pledger
W J
WJ
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002455:Cell Division; D002478:Cells, Cultured; D003470:Culture Media; D016895:Culture Media, Serum-Free; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D016193:G1 Phase; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000502:physiology*; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D003470:Culture Media; D016895:Culture Media, Serum-Free; D019925:Cyclin A; D019927:Cyclin E; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases