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首页> 外文期刊>Molecular and Cellular Biology >Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases.
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Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases.

机译：Fas激活p38丝裂原活化的蛋白激酶信号传导途径需要ICE / CED-3家族的蛋白酶。

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The Fas receptor mediates a signalling cascade resulting in programmed cell death (apoptosis) within hours of receptor cross-linking. In this study Fas activated the stress-responsive mitogen-activated protein kinases, p38 and JNK, within 2 h in Jurkat T lymphocytes but not the mitogen-responsive kinase ERK1 or pp70S6k. Fas activation of p38 correlated temporally with the onset of apoptosis, and transfection of constitutively active MKK3 (glu), an upstream regulator of p38, potentiated Fas-induced cell death, suggesting a potential involvement of the MKK3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown to require ICE (interleukin-1 beta-converting enzyme) family proteases to induce apoptosis from studies utilizing the cowpox ICE inhibitor protein CrmA, the synthetic tetrapeptide ICE inhibitor YVAD-CMK, and the tripeptide pan-ICE inhibitor Z-VAD-FMK. In this study, crmA antagonized, and YVAD-CMK and Z-VAD-FMK completely inhibited, Fas activation of p38 kinase activity, demonstrating that Fas-dependent activation of p38 requires ICE/CED-3 family members and conversely that the MKK3/p38 activation cascade represents a downstream target for the ICE/CED-3 family proteases. Intriguingly, p38 activation by sorbitol and etoposide was resistant to YVAD-CMK and Z-VAD-FMK, suggesting the existence of an additional mechanism(s) of p38 regulation. The ICE/CED-3 family-p38 regulatory relationship described in the current work indicates that in addition to the previously described destructive cleavage of substrates such as poly(ADP ribose) polymerase, lamins, and topoisomerase, the apoptotic cysteine proteases also function to regulate stress kinase signalling cascades.
机译：Fas受体介导信号传导级联反应，导致受体交联后数小时内程序性细胞死亡（细胞凋亡）。在这项研究中，Fas激活了Jurkat T淋巴细胞中2小时内应激反应的促丝裂原活化蛋白激酶p38和JNK，但未激活丝裂原反应性激酶ERK1或pp70S6k。 p38的Fas激活在时间上与凋亡的发生和p38的上游调节剂组成性活性MKK3（glu）的转染相关，可增强Fas诱导的细胞死亡，提示MKK3 / p38激活途径可能参与了Fas介导的活动。细胞凋亡。从利用牛痘ICE抑制剂蛋白CrmA，合成四肽ICE抑制剂YVAD-CMK和三肽pan-ICE抑制剂Z-VAD进行的研究中，已证明Fas需要ICE（白介素-1β转化酶）家族蛋白酶来诱导细胞凋亡。 -FMK。在这项研究中，crmA拮抗，并且YVAD-CMK和Z-VAD-FMK完全抑制p38激酶活性的Fas激活，表明p38的Fas依赖性激活需要ICE / CED-3家族成员，而相反，MKK3 / p38激活级联反应代表ICE / CED-3家族蛋白酶的下游目标。有趣的是，山梨糖醇和依托泊苷对p38的激活对YVAD-CMK和Z-VAD-FMK有抵抗力，表明存在p38调控的其他机制。当前工作中描述的ICE / CED-3家族-p38调节关系表明，除了先前描述的底物如聚ADP核糖聚合酶，lamins和拓扑异构酶的破坏性切割，凋亡的半胱氨酸蛋白酶还具有调节应激激酶信号传导级联。

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