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Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway
E Goillot1, J Raingeaud, A Ranger
1Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Abstract:
Ligation of the cell surface receptor Fas/APO-1 (CD95) by its specific ligand or by anti-Fas antibodies rapidly induces apoptosis in susceptible cells. To characterize the molecular events involved in Fas-induced apoptosis, we examined the contribution of two subgroups of the mitogen-activated protein (MAP) kinase family, the Jun kinases or stress-activated protein kinases (JNKs/SAPKs) and the extracellular signal-regulated kinases (ERKs), in a Fas-sensitive neuroblastoma cell line. Here we show that both JNK and ERK protein kinases were activated upon Fas crosslinking through a Ras-dependent mechanism. Interference with either the JNK or ERK pathway by ectopic expression of dominant-interfering mutant proteins blocked Fas-mediated apoptosis. ERK activation was transient and associated with induced expression of the Fas receptor. In contrast, JNK activation was sustained and correlated with the onset of apoptosis. These data indicate that the ERK and the JNK groups of MAP kinases cooperate in the induction of cell death by Fas. Inhibition of Fas killing by an interleukin 1beta-converting enzyme (ICE)-like protease inhibitor peptide did not modify Fas-induced JNK activation upon Fas ligation. In contrast, changes in Bcl-2 level due to expression of sense and antisense vectors influenced the sensitivity to Fas killing and Fas-induced JNK activation.
Insights
Fas receptor ligation triggers apoptosis via Ras-dependent activation of both Jun kinases (JNKs) and extracellular signal-regulated kinases (ERKs). These MAP kinase pathways cooperate to induce cell death, with sustained JNK activation correlating with apoptosis onset.
Area of Science:
- Cellular Biology
- Molecular Biology
- Neuroscience
Background:
- The Fas receptor (CD95) is a key mediator of apoptosis, a programmed cell death process.
- Mitogen-activated protein (MAP) kinases, including JNKs and ERKs, are involved in cellular signaling pathways.
- Understanding the role of MAP kinases in Fas-induced apoptosis is crucial for deciphering cell death mechanisms.
Purpose of the Study:
- To investigate the involvement of Jun kinases (JNKs/SAPKs) and extracellular signal-regulated kinases (ERKs) in Fas-mediated apoptosis.
- To elucidate the molecular mechanisms underlying Fas-induced cell death in a neuroblastoma cell line.
Main Methods:
- Utilized a Fas-sensitive neuroblastoma cell line.
- Examined JNK and ERK activation upon Fas receptor crosslinking.
- Employed dominant-interfering mutant proteins to block specific kinase pathways.
- Assessed the impact of interleukin 1beta-converting enzyme (ICE)-like protease inhibitors and Bcl-2 levels on Fas signaling.
Main Results:
- Fas crosslinking activated both JNK and ERK pathways in a Ras-dependent manner.
- Inhibition of either JNK or ERK signaling abrogated Fas-mediated apoptosis.
- ERK activation was transient and linked to increased Fas receptor expression.
- JNK activation was sustained and correlated with the initiation of apoptosis.
- ICE-like protease inhibition did not affect JNK activation, while Bcl-2 levels modulated Fas sensitivity and JNK activation.
Conclusions:
- The ERK and JNK MAP kinase pathways collaborate to induce Fas-mediated apoptosis.
- Sustained JNK activation is a critical event in the execution of Fas-induced cell death.
- Bcl-2 protein levels play a role in regulating sensitivity to Fas-induced apoptosis and JNK activation.