The absence of NF-κB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis

F Tang, G Tang, J Xiang, Q Dai… - Molecular and cellular …, 2002 - Taylor & Francis
F Tang, G Tang, J Xiang, Q Dai, MR Rosner, A Lin
Molecular and cellular biology, 2002Taylor & Francis
The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune
responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological
activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-
terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the
transcription factor NF-κB, whose target genes include those that encode inhibitors of both
caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able …
The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-α-induced apoptosis is incompletely understood. Here we report that in TNF-α-sensitive cells activation of the IKK/NF-κB pathway fails to block TNF-α-induced apoptosis, although its inactivation still promotes TNF-α-induced apoptosis. Interestingly, TNF-α-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-α was transient in TNF-α-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-α-induced apoptosis. Thus, absence of NF-κB-mediated inhibition of JNK activation contributes to TNF-α-induced apoptosis.
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