Negative Regulation of JNK Signaling by the Tumor Suppressor CYLD

Abstract

CYLD is a tumor suppressor that is mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple tumors of the skin appendages. Recent studies suggest that transfected CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-B. However, the role of endogenous CYLD in regulating cell signaling remains poorly defined. Here we report a critical role for CYLD in negatively regulating the c-Jun NH 2 -terminal kinase (JNK). CYLD knockdown by RNA interference results in hyperactivation of JNK by diverse immune stimuli, including tumor necrosis factor-␣, interleukin-1, lipopolysaccharide, and an agonistic anti-CD40 antibody. The JNKinhibitory function of CYLD appears to be specific for immune receptors because the CYLD knockdown has no significant effect on stress-induced JNK activation. Consistently, CYLD negatively regulates the activation of MKK7, an upstream kinase known to mediate JNK activation by immune stimuli. We further demonstrate that CYLD also negatively regulates IB kinase, although this function of CYLD is seen in a receptor-dependent manner. These findings identify the JNK signaling pathway as a major downstream target of CYLD and suggest a receptor-dependent role of CYLD in regulating the IB kinase pathway.

Mutations in the NF-κB signaling pathway: implications for human disease

“…Dysregulation of both classes of NF-kB targets would be expected to participate in cylindroma formation. Nevertheless, it cannot be ruled out that effects on other signaling pathways, which are under CYLD control, such as the c-Jun N-terminal kinase pathway (Reiley et al, 2004), also play a role in cylindromatosis.…”

Current insights into the regulation of programmed cell death by NF-κB

“…Studies have shown that ER stress promotes NF-kB-dependent activation of TNFa expression via association of IKK with the ER stress sensor IRE1a and TRAF2, whereas simultaneous downregulation of TRAF2 impairs activation of NF-kB and JNK greatly potentiates the toxic effect of TNFa (Hu et al, 2006a). Another way in which NF-kB can enhance cell death is via upregulation of the tumor suppressor CYLD that acts as a deubiquitinase to remove K63 polyubiquitin chains from TRAF2/6 and NEMO, leading to disassembly of the IKK complex, termination of NF-kB signaling and enhanced cell death (Brummelkamp et al, 2003;Kovalenko et al, 2003;Jono et al, 2004;Reiley et al, 2004). CYLD also deubiquitinates the p50 and p52 coactivator Bcl-3 to suppress activation of genes that promote cell proliferation and tumor growth (Ikeda and Dikic, 2006;Massoumi et al, 2006).…”

NF-κB-related genetic diseases

“…It has been recently shown to be under CYLD control, via the effect of this deubiquitinase on TRAF2 or TRAF6. 73 Therefore, cylindromatosis is unlikely to be a 'pure' NF-kB-related pathology.…”