Negative regulation of JNK signaling by the tumor suppressor CYLD

被引:126
作者
Reiley, W [1 ]
Zhang, MY [1 ]
Sun, SC [1 ]
机构
[1] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA
关键词
D O I
10.1074/jbc.M411049200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappaB. 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 NH2-terminal kinase (JNK). CYLD knockdown by RNA interference results in hyperactivation of JNK by diverse immune stimuli, including tumor necrosis factor-alpha, interleukin-1, lipopolysaccharide, and an agonistic anti-CD40 antibody. The JNK-inhibitory 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 IkappaB 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 IkappaB kinase pathway.
引用
收藏
页码:55161 / 55167
页数:7
相关论文
共 56 条
[51]   TAK1 is a ubiquitin-dependent kinase of MKK and IKK [J].
Wang, C ;
Deng, L ;
Hong, M ;
Akkaraju, GR ;
Inoue, J ;
Chen, ZJJ .
NATURE, 2001, 412 (6844) :346-351
[52]   De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling [J].
Wertz, IE ;
O'Rourke, KM ;
Zhou, HL ;
Eby, M ;
Aravind, L ;
Seshagiri, S ;
Wu, P ;
Wiesmann, C ;
Baker, R ;
Boone, DL ;
Ma, A ;
Koonin, EV ;
Dixit, VM .
NATURE, 2004, 430 (7000) :694-699
[53]  
Xu X, 1996, ONCOGENE, V13, P135
[54]  
Yang YM, 2003, CLIN CANCER RES, V9, P391
[55]   Early lethality, functional NF-kappa B activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice [J].
Yeh, WC ;
Shahinian, A ;
Speiser, D ;
Kraunus, J ;
Billia, F ;
Wakeham, A ;
delaPompa, JL ;
Ferrick, D ;
Hum, B ;
Iscove, N ;
Ohashi, P ;
Rothe, M ;
Goeddel, DV ;
Mak, TW .
IMMUNITY, 1997, 7 (05) :715-725
[56]   NF-κB RelA poses epidermal proliferation riven by TNFR1 and JNK [J].
Zhang, JY ;
Green, CL ;
Tao, SY ;
Khavari, PA .
GENES & DEVELOPMENT, 2004, 18 (01) :17-22