Segregation of NF-κB activation through NEMO/IKKγ by Tax and TNFα: implications for stimulus-specific interruption of oncogenic signaling
| Autor: | Jean Marie Peloponese, Akiko Miyazato, Karen V. Kibler, Venkat R. K. Yedavalli, Hidekatsu Iha, Kerstin Haller, Kuan-Teh Jeang, Takefumi Kasai |
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| Přispěvatelé: | Arizona State University [Tempe] (ASU), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Molecular Virology Section, Laboratory of Molecular Microbiology, National Institutes of Health |
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Cancer Research
congenital hereditary and neonatal diseases and abnormalities Molecular Sequence Data IκB kinase Protein Serine-Threonine Kinases Biology Proinflammatory cytokine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics Animals Humans Amino Acid Sequence skin and connective tissue diseases Molecular Biology 030304 developmental biology 0303 health sciences Tumor Necrosis Factor-alpha Kinase NF-kappa B I-Kappa-B Kinase Antibodies Monoclonal NF-κB Gene Products tax I-kappa B Kinase Cell biology [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology chemistry 030220 oncology & carcinogenesis Knockout mouse [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology Tumor necrosis factor alpha Trans-acting Sequence Alignment |
| Zdroj: | Oncogene Oncogene, Nature Publishing Group, 2003, 22 (55), pp.8912-8923. ⟨10.1038/sj.onc.1207058⟩ |
| ISSN: | 0950-9232 1476-5594 |
| Popis: | International audience; Nuclear factor-kappaB essential modulator (NEMO), also called IKKgamma, has been proposed as a 'universal' adaptor of the I-kappaB kinase (IKK) complex for stimuli such as proinflammatory cytokines, microbes, and the HTLV-I Tax oncoprotein. Currently, it remains unclear whether the many signals that activate NF-kappaB through NEMO converge identically or differently. We have adopted two approaches to answer this question. First, we generated and targeted intracellularly three NEMO-specific monoclonal antibodies (mAbs). These mAbs produced two distinct intracellular NF-kappaB inhibition profiles segregating TNFalpha from Tax activation. Second, using NEMO knockout mouse fibroblasts and 10 NEMO mutants, we found that different regions function in trans either to complement or to inhibit dominantly TNFalpha, IL-1beta, or Tax activation of NF-kappaB. For instance, NEMO (1-245 amino acids) supported Tax-mediated NF-kappaB activation, but did not serve TNFalpha- or IL-1beta signaling. Altogether, our findings indicate that while NEMO 'universally' adapts numerous NF-kappaB activators, it may do so through separable domains. We provide the first evidence that selective targeting of NEMO can abrogate oncogenic Tax signaling without affecting signals used for normal cellular metabolism. |
| Databáze: | OpenAIRE |
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