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Published on: March 27, 2020

Negative regulation of JNK signaling by the tumor suppressor CYLD

William Reiley1, Minying Zhang, Shao-Cong Sun

  • 1Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

The Journal of Biological Chemistry
|October 22, 2004
PubMed

Insights

The tumor suppressor CYLD negatively regulates the c-Jun NH(2)-terminal kinase (JNK) pathway. CYLD knockdown leads to JNK hyper-activation by immune stimuli, identifying JNK as a key target.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Oncology

Background:

  • CYLD is a tumor suppressor gene implicated in familial cylindromatosis.
  • Recent studies suggest CYLD possesses deubiquitinating enzyme activity and inhibits NF-kappaB activation.
  • The precise role of endogenous CYLD in regulating cellular signaling pathways is not fully understood.

Purpose of the Study:

  • To investigate the role of endogenous CYLD in regulating cell signaling pathways.
  • To determine if CYLD negatively regulates the c-Jun NH(2)-terminal kinase (JNK) signaling pathway.
  • To elucidate the specificity of CYLD's regulatory functions in response to different stimuli.

Main Methods:

  • RNA interference (RNAi) was used to knock down CYLD expression.
  • Cells were stimulated with various immune stimuli, including tumor necrosis factor-alpha, interleukin-1, lipopolysaccharide, and anti-CD40 antibody.
  • Activation of JNK, MKK7, and IkappaB kinase was assessed.

Main Results:

  • CYLD knockdown resulted in hyper-activation of JNK in response to immune stimuli.
  • CYLD's inhibitory effect on JNK was specific to immune receptor activation, not stress-induced activation.
  • CYLD was found to negatively regulate MKK7 and, in a receptor-dependent manner, IkappaB kinase activation.

Conclusions:

  • CYLD plays a critical role in negatively regulating the JNK signaling pathway, particularly in response to immune receptor activation.
  • The JNK pathway is a major downstream target of CYLD.
  • CYLD exhibits a receptor-dependent role in modulating the IkappaB kinase pathway.

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