IRF-2 regulates NF-kappaB activity by modulating the subcellular localization of NF-kappaB

Abstract

5221 Nuclear Factor-kappa B (NF-κB) is a transcription factor essential to the control of cell proliferation, survival, differentiation, immune response, and inflammation. Constitutive NF-κB activation has been observed in a broad variety of solid tumors and hematological malignancies, which suggests that NF-κB signaling may perform a critical role in the development of human cancers. Interferon regulatory factor-2 (IRF-2), an antagonistic transcriptional repressor of IRF-1, evidences oncogenic potential, but little is currently known regarding the mechanism underlying the oncogenic activities of IRF-2. In this study, we report that IRF-2 recruits RelA/p65 transcription factors into the nucleus via physical interaction. While the nuclear recruitment of RelA by IRF-2 augments TNFα-induced NF-κB dependent transcription, the N-terminal truncated mutant form of IRF-2 inhibits the nuclear localization of RelA, and thus interferes with NF-κB activation. Furthermore, the knockdown of IRF-2 by IRF-2 siRNA attenuates TNFα-induced NF-κB dependent transcription by inhibiting the nuclear localization of RelA. Thus, these results show that IRF-2 regulates NF-κB activity via the modulation of NF-κB subcellular localization.