Open AccessSegregation of NF-κB activation through NEMO/IKKγ by Tax and TNFα: implications for stimulus-specific interruption of oncogenic signaling
Author(s) -
Hidekatsu Iha,
Karen V. Kibler,
Venkat R. K. Yedavalli,
Jean Marie Peloponese,
Kerstin Haller,
Akiko Miyazato,
Takefumi Kasai,
Kuan Teh Jeang
Publication year - 2003
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/sj.onc.1207058
Subject(s) - iκb kinase , biology , nf κb , proinflammatory cytokine , signal transduction , microbiology and biotechnology , tumor necrosis factor alpha , signal transducing adaptor protein , nfkb1 , intracellular , kinase , phosphorylation , cancer research , transcription factor , immunology , genetics , inflammation , gene
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.