Activation-induced T-cell death is cell cycle dependent and regulated by cyclin B.
Developing thymocytes and some T-cell hybridomas undergo activation-dependent programmed cell death. Although recent studies have identified some critical regulators in programmed cell death, the role of cell cycle regulation in activation-induced cell death in T cells has not been addressed. We demonstrate that synchronized T-cell hybridomas, irrespective of the point in the cell cycle at which they are activated, stop cycling shortly after they reach G2/M. These cells exhibit the diagnostic characteristics of apoptotic cell death. Although p34cdc2 levels are not perturbed after activation of synchronously cycling T cells, cyclin B- and p34cdc2-associated histone H1 kinase activity is persistently elevated. This activation-dependent induction of H1 kinase activity in T cells is associated with a decrease in the phosphotyrosine content of p34cdc2. We also demonstrate that transient inappropriate coexpression of cyclin B with p34cdc2 induces DNA fragmentation in a heterologous cell type. Finally, in T cells, cyclin B-specific antisense oligonucleotides suppress activation-induced cell death but not cell death induced by exposure to dexamethasone. We therefore conclude that a persistent elevation of the level of cyclin B kinase is required for activation-induced programmed T-cell death.
Fotedar
R
R
Institut de Biologie Structurale J.-P. Ebel, Grenoble, France.
Flatt
J
J
Gupta
S
S
Margolis
R L
RL
Fitzgerald
P
P
Messier
H
H
Fotedar
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death / Q000187:drug effects; D003208:Concanavalin A; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004247:DNA / Q000032:analysis; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D006825:Hybridomas; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology; D006656:Protamine Kinase / Q000378:metabolism; D011817:Rabbits; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D016213:Cyclins; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D003208:Concanavalin A; D004247:DNA; D006656:Protamine Kinase; D016203:CDC2 Protein Kinase