JNK (c-Jun N-terminal kinase) and p38 activation in receptor-mediated and chemically-induced apoptosis of T-cells: differential requirements for caspase activation
JNK (c-Jun N-terminal kinase) and p38 activation in receptor-mediated and chemically-induced apoptosis of T-cells: differential requirements for caspase activation
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DOI：
10.1042/0264-6021:3480093
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发表时间：
2000-05-15
影响因子：
4.1
通讯作者：
Dickens, M
中科院分区：
文献类型：
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作者：
MacFarlane, M;Cohen, GM;Dickens, M
应激活化的丝裂原活化蛋白激酶（MAP激酶）、c-Jun N-末端激酶（JNK）和p38的活化是诱导神经元细胞凋亡所必需的;然而，在其他细胞类型中，它们的参与可能是刺激依赖性的。在本研究中，我们研究JNK和p38在一个单一的非神经元细胞类型的激活，经历受体介导的（肿瘤坏死因子相关的凋亡诱导配体和CD 95）或化学诱导的（lactacystin）凋亡。在Jurkat T细胞中，受体介导的和化学诱导的细胞凋亡分别导致起始半胱天冬酶-8和-9的时间依赖性激活。这两种刺激都导致JNK和p38的显著激活，这与凋亡的时间依赖性诱导密切相关。半胱天冬酶抑制剂苄氧羰基-Val-Ala-Asp-（OMe）氟甲基酮（z-VAD.FMK）抑制受体介导的细胞凋亡并抑制JNK和p38的激活。相反，通过磷脂酰丝氨酸暴露和聚（ADP-核糖）聚合酶裂解评估，用z-VAD.FMK抑制乳胱氨酸诱导的细胞凋亡，并不抑制JNK或p38的活化，表明在化学诱导的细胞凋亡过程中，JNK和p38的活化不依赖于效应物半胱天冬酶。使用特异性p38抑制剂SB 203580评估p38在细胞凋亡中的作用。未观察到对诱导细胞凋亡或半胱天冬酶活化的影响，但抑制了促分裂原活化蛋白激酶活化蛋白激酶-2（MAPKAPK-2）（p38的直接下游靶点）的活化。因此，p38活化和MAPKAPK-2活化对于诱导受体或化学诱导的细胞凋亡都不是关键的。因此，在单个细胞类型中，（1）凋亡期间p38和JNK活化的机制是刺激依赖性的，（2）通过磷脂酰丝氨酸暴露评估，p38途径的活化不是胱天蛋白酶活化或凋亡所必需的，但可能仍然需要引起凋亡表型的其他特征。
Activation of the stress-activated mitogen-activated protein kinases (MAP kinases), c-Jun N-terminal kinase (JNK) and p38, is necessary for the induction of apoptosis in neuronal cells; however, in other cell types their involvement may be stimulus-dependent. In the present study we investigate the activation of JNK and p38 in a single non-neuronal cell type, undergoing receptor-mediated (tumour necrosis factor-related apoptosis-inducing ligand and CD95) or chemically-induced (lactacystin) apoptosis. In Jurkat T-cells, receptor-mediated and chemically-induced apoptosis resulted in a time-dependent activation of the initiator caspases-8 and -9, respectively. Both types of stimuli resulted in a significant activation of JNK and p38, which closely paralleled the time-dependent induction of apoptosis. The caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone (z-VAD.FMK) inhibited receptor-mediated apoptosis and suppressed JNK and p38 activation. In contrast, inhibition of lactacystin-induced apoptosis with z-VAD.FMK, as assessed by phosphatidylserine exposure and poly(ADP-ribose) polymerase cleavage, did not inhibit activation of JNK or p38, demonstrating that during chemically-induced apoptosis, activation of JNK and p38 is independent of effector caspases. The role of p38 in apoptosis was assessed using the specific p38 inhibitor, SB203580. No effect on the induction of apoptosis or caspase activation was observed, although activation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK-2), an immediate downstream target of p38, was inhibited. Therefore neither p38 activation nor activation of MAPKAPK-2 is critical for induction of either receptor- or chemically-induced apoptosis. Thus, within a single cell type, (1) the mechanism of p38 and JNK activation during apoptosis is stimulus-dependent and (2) activation of the p38 pathway is not required for caspase activation or apoptosis, assessed by phosphatidylserine exposure, but may still be required to elicit other features of the apoptotic phenotype.