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- Title
Gadd45ß mediates the NF-?B suppression of JNK signalling by targeting MKK7/JNKK2.
- Authors
Zazzeroni, Francesca; Bubici, Concetta; Jayawardena, Shanthi; Alvarez, Kellean; Matsuda, Shuji; Melis, Tiziana; Wei-Jen Tang; D'Adamio, Luciano; Franzoso, Guido; Papa, Salvatore; Nguyen, Dung U.; Pham, Can G.; Nelsbach, Andreas H.; De Smaele, Enrico
- Abstract
NF-?B/Rel transcription factors control apoptosis, also known as programmed cell death. This control is crucial for oncogenesis, cancer chemo-resistance and for antagonizing tumour necrosis factor a (TNFa)-induced killing. With regard to TNFa, the anti-apoptotic activity of NF-?B involves suppression of the c-Jun N-terminal kinase (JNK) cascade. Using an unbiased screen, we have previously identified Gadd45ß/Myd118, a member of the Gadd45 family of inducible factors, as a pivotal mediator of this suppressive activity of NF-?B. However, the mechanisms by which Gadd45ß inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 - a specific and essential activator of JNK - as a target of Gadd45ß, and in fact, of NF-?B itself. Gadd45ß binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-?B and JNK pathways. Importantly, Gadd45ß is required to antagonize TNFa-induced cytotoxicity, and peptides disrupting the Gadd45ß/MKK7 interaction hinder the ability of Gadd45ß, as well as of NF-?B, to suppress this cytotoxicity. These findings establish a basis for the NF-?B control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.
- Publication
Nature Cell Biology, 2004, Vol 6, Issue 2, p146
- ISSN
1465-7392
- Publication type
Academic Journal
- DOI
10.1038/ncb1093