Fotedar R, Flatt J, Gupta S, Margolis R L, Fitzgerald P, Messier H, Fotedar A
Institut de Biologie Structurale J.-P. Ebel, Grenoble, France.
Mol Cell Biol. 1995 Feb;15(2):932-42. doi: 10.1128/MCB.15.2.932.
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.
正在发育的胸腺细胞和一些T细胞杂交瘤会经历激活依赖性程序性细胞死亡。尽管最近的研究已经确定了程序性细胞死亡中的一些关键调节因子，但细胞周期调控在T细胞激活诱导的细胞死亡中的作用尚未得到探讨。我们证明，同步化的T细胞杂交瘤，无论其在细胞周期的哪个点被激活，在到达G2/M期后不久就会停止循环。这些细胞表现出凋亡性细胞死亡的诊断特征。尽管同步循环的T细胞激活后p34cdc2水平未受干扰，但细胞周期蛋白B和与p34cdc2相关的组蛋白H1激酶活性持续升高。T细胞中这种激活依赖性的H1激酶活性诱导与p34cdc2磷酸酪氨酸含量的降低有关。我们还证明，细胞周期蛋白B与p34cdc2的短暂不适当共表达会在异源细胞类型中诱导DNA片段化。最后，在T细胞中，细胞周期蛋白B特异性反义寡核苷酸可抑制激活诱导的细胞死亡，但不能抑制地塞米松诱导的细胞死亡。因此，我们得出结论，细胞周期蛋白B激酶水平的持续升高是激活诱导的程序性T细胞死亡所必需的。
