The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-xL

The transcription factors of the Rel/NF-kappa B family are key regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the Rel/NF-kappa B oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-kappa B control. Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-kappa B raised the issue of whether NF-kappa B is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate that NF-kappa B differentially regulates the expression of particular Bcl-2-related death inhibitors and that it directly activates the expression of Bcl-x(L). While Bcl-x(L) was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-kappa B factors also upregulated bcl-x gene expression and this effect was antagonized by an inhibitor of NF-kappa B activity. The expression of bcl-x suppressed apoptosis in the presence or absence of NF-kappa B activity. Functional analysis of the bcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-kappa B directly regulates the expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-x(L) and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with aberrant Rel/NF-kappa B activity.