Roulston A, Reinhard C, Amiri P, Williams L T
Chiron Technologies, Chiron Corporation, Emeryville, California 94608, USA.
J Biol Chem. 1998 Apr 24;273(17):10232-9. doi: 10.1074/jbc.273.17.10232.
Fas ligand and tumor necrosis factor alpha (TNF) bind to members of the TNF receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF induces multiple effects including proliferation, differentiation, and apoptosis. Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas receptor cross-linking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic kinetics. The first phase is transient, precedes apoptosis, and is caspase-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 kinase (but not Mek) are necessary to protect cells from TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF plays a key role in regulating apoptosis.
Fas配体和肿瘤坏死因子α（TNF）与TNF受体超家族的成员结合。Fas配体刺激导致细胞凋亡，而TNF诱导多种效应，包括增殖、分化和细胞凋亡。c-Jun氨基末端激酶（JNK）和p38激酶途径的激活是Fas和TNF信号传导的共同特征；然而，它们在细胞凋亡中的作用存在争议。Fas受体交联在没有放线菌素D的情况下诱导细胞凋亡，并以半胱天冬酶依赖性方式激活JNK。相比之下，TNF诱导细胞凋亡需要放线菌素D，并以双相动力学激活JNK和p38激酶。第一阶段是短暂的，先于细胞凋亡，且不依赖半胱天冬酶，而第二阶段与细胞凋亡同时发生，且依赖半胱天冬酶。使用MKK4/MKK6突变体或p38抑制剂SB203580抑制早期TNF诱导的JNK和p38激酶会增加TNF诱导的细胞凋亡，而野生型MKK4/MKK6的表达则提高细胞存活率。相比之下，Mek抑制剂PD098059对细胞存活没有影响。这些结果表明，p38激酶（而非Mek）的早期激活对于保护细胞免受TNF介导的细胞毒性是必要的。因此，TNF引发的早期应激激酶激活在调节细胞凋亡中起关键作用。
