Transcriptional Activation by NF-κB Requires Multiple Coactivators

Abstract

Nuclear factor-κB (NF-κB) plays a role in the transcriptional regulation of genes involved in inflammation and cell survival. In this report we demonstrate that NF-κB recruits a coactivator complex that has striking similarities to that recruited by nuclear receptors. Inactivation of either cyclic AMP response element binding protein (CREB)-binding protein (CBP), members of the p160 family of coactivators, or the CBP-associated factor (p/CAF) by nuclear antibody microinjection prevents NF-κB-dependent transactivation. Like nuclear receptor-dependent gene expression, NF-κB-dependent gene expression requires specific LXXLL motifs in one of the p160 family members, and enhancement of NF-κB activity requires the histone acetyltransferase (HAT) activity of p/CAF but not that of CBP. This coactivator complex is differentially recruited by members of the Rel family. The p50 homodimer fails to recruit coactivators, although the p50-p65 heterodimeric form of the transcription factor assembles the integrator complex. These findings provide new mechanistic insights into how this family of dimeric transcription factors has a differential effect on gene expression.

ACKNOWLEDGMENTS

We thank Yoshihiro Nakatani, Michael Stallcup, William Chin, and Myles Brown for providing the indicated reagents. We acknowledge the insightful comments and advice provided by Lou Schiltz and Akira Takeshita. Amy Williams assembled constructs used in some of these studies, and her efforts are appreciated. Kay Case provided excellent assistance with some of the cell culture.

This work was supported by research grants from the National Institutes of Health to D.T., C.K.G., M.G.R., and T.C. D.T. is a member of the Pew Scholars Program, C.K.G., is an Established Investigator of the American Heart Association, and M.G.R. is an Investigator in the Howard Hughes Medical Institute.