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Identification of a human NF-κB-activating protein, TAB3

The NF-κB pathway plays a critical role in regulating cellular processes such as immune responses, stress responses, apoptosis, proliferation and differentiation, whereas dysfunction of this pathway has been associated with numerous cancer and immune disorders. We have applied our Random Activation of Gene Expression technology to an NF-κB reporter cell line to facilitate the discovery of positive regulators of NF-κB activation. A small protein expression library, corresponding to ≈0.1× genome coverage, was generated and screened for clones exhibiting constitutive activation of NF-κB. After isolation of cellular clones displaying the relevant phenotypes, we identified two known components of the NF-κB pathway and a hypothetical gene that we have designated the human ortholog of Xenopus TAK1-binding protein 3 (TAB3). Overexpression of human TAB3 was found to activate both NF-κB and AP-1 transcription factors. Furthermore, the activation of NF-κB by TAB3 was blocked by the NF-κB inhibitor, SN50, and by expression of dominant-negative forms of tumor necrosis factor α-associated factor 6 and transforming growth factor β-activated kinase. Taken together, these data demonstrate that TAB3 transforming growth factor is a constituent of the NF-κB pathway functioning upstream of tumor necrosis factor α-associated factor 6/transforming growth factor β-activated kinase. Interestingly, increased expression of TAB3 was found in some cancer tissues, and its overexpression in NIH 3T3 cells resulted in cellular transformation, thus establishing a causative link between elevated TAB3 expression, constitutive NF-κB activation, and oncogenesis.