| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Nature Cell Biology; Feb2004, Vol. 6 Issue 2, following p146-153, 8p, 30 Color Photographs, 36 Diagrams, 25 Graphs |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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