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  • The EMBO Journal (2006) 25, 5549 - 5559
  • doi:10.1038/sj.emboj.7601423

Published online: 16 November 2006

An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway

Akihito Nakajima1, Sachiko Komazawa-Sakon1, Mutsuhiro Takekawa2, Tomonari Sasazuki1, Wen-Chen Yeh3, Hideo Yagita1, Ko Okumura1 and Hiroyasu Nakano1

  1. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
  2. Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  3. Campbell Family Institute for Breast Cancer Research, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Correspondence to:

Hiroyasu Nakano, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: +81 3 5802 1045; Fax: +81 3 3813 0421; E-mail: hnakano@med.juntendo.ac.jp

Received 8 July 2006; Accepted 4 October 2006

Inhibition of NF-kappaB activation increases susceptibility to tumor necrosis factor (TNF)alpha-induced cell death, concurrent with caspases and prolonged c-Jun N-terminal kinase (JNK) activation, and reactive oxygen species (ROS) accumulation. However, the detailed mechanisms are unclear. Here we show that cellular FLICE-inhibitory protein (c-FLIP) is rapidly lost in NF-kappaB activation-deficient, but not wild-type fibroblasts upon TNFalpha stimulation, indicating that NF-kappaB normally maintains the cellular levels of c-FLIP. The ectopic expression of the long form of c-FLIP (c-FLIPL) inhibits TNFalpha-induced prolonged JNK activation and ROS accumulation in NF-kappaB activation-deficient fibroblasts. Conversely, TNFalpha induces prolonged JNK activation and ROS accumulation in c-Flip-/- fibroblasts. Moreover, c-FLIPL directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFalpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFbeta-activated kinase 1. This stimuli-dependent interaction of c-FLIPL with MKK7 might selectively suppress the prolonged phase of JNK activation. Taken that ROS promote JNK activation and activation of the JNK pathway may promote ROS accumulation, c-FLIPL might block this positive feedback loop, thereby suppressing ROS accumulation.

  • Keywords:

    • c-FLIP,
    • c-Jun N-terminal kinase,
    • NF-kappaB,
    • reactive oxygen species,
    • tumor necrosis factor