Tran S E, Holmstrom T H, Ahonen M, Kahari V M, Eriksson J E
Turku Centre for Biotechnology, POB 123, FIN-20521, University of Turku, Turku, Finland.
J Biol Chem. 2001 May 11;276(19):16484-90. doi: 10.1074/jbc.M010384200. Epub 2001 Jan 25.
The tumor necrosis factor (TNF), Fas, and TNF-related apoptosis-inducing ligand (TRAIL) receptors (R) are highly specific physiological mediators of apoptotic signaling. We observed earlier that a number of FasR-insensitive cell lines could redirect the proapoptotic signal to an anti-apoptotic ERK1/2 signal resulting in inhibition of caspase activation. Here we determine that similar mechanisms are operational in regulating the apoptotic signaling of other death receptors. Activation of the FasR, TNF-R1, and TRAIL-R, respectively, rapidly induced subsequent ERK1/2 activation, an event independent from caspase activity. Whereas inhibition of the death receptor-mediated ERK1/2 activation was sufficient to sensitize the cells to apoptotic signaling from FasR and TRAIL-R, cells were still protected from apoptotic TNF-R1 signaling. The latter seemed to be due to the strong activation of the anti-apoptotic factor NF-kappaB, which remained inactive in FasR or TRAIL-R signaling. However, when the cells were sensitized with cycloheximide, which is sufficient to sensitize the cells also to apoptosis by TNF-R1 stimulation, we noticed that adenovirus-mediated expression of constitutively active MKK1 could rescue the cells from apoptosis induced by the respective receptors by preventing caspase-8 activation. Taken together, our results show that ERK1/2 has a dominant protecting effect over apoptotic signaling from the death receptors. This protection, which is independent of newly synthesized proteins, acts in all cases by suppressing activation of the caspase effector machinery.
肿瘤坏死因子（TNF）、Fas和TNF相关凋亡诱导配体（TRAIL）受体（R）是凋亡信号高度特异性的生理介质。我们之前观察到，一些对FasR不敏感的细胞系可将促凋亡信号重定向为抗凋亡的ERK1/2信号，从而抑制半胱天冬酶激活。在此，我们确定类似机制在调节其他死亡受体的凋亡信号中也起作用。分别激活FasR、TNF-R1和TRAIL-R后，会迅速诱导随后的ERK1/2激活，这一事件独立于半胱天冬酶活性。虽然抑制死亡受体介导的ERK1/2激活足以使细胞对来自FasR和TRAIL-R的凋亡信号敏感，但细胞仍受到保护，免受TNF-R1凋亡信号的影响。后者似乎是由于抗凋亡因子NF-κB的强烈激活，而NF-κB在FasR或TRAIL-R信号中保持无活性。然而，当用环己酰亚胺使细胞敏感化时（环己酰亚胺也足以使细胞对TNF-R1刺激诱导的凋亡敏感），我们注意到腺病毒介导的组成型活性MKK1的表达可通过阻止半胱天冬酶-8激活，使细胞从各自受体诱导的凋亡中获救。综上所述，我们的结果表明，ERK1/2对死亡受体的凋亡信号具有主导性保护作用。这种保护作用独立于新合成的蛋白质，在所有情况下均通过抑制半胱天冬酶效应机制的激活来发挥作用。
