Human T-Cell Lymphotropic Virus Type 1 Tax Represses c-Myb-Dependent Transcription through Activation of the NF-κB Pathway and Modulation of Coactivator Usage

Abstract

The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation. Aberrant c-Myb activity has been reported for numerous human cancers, and enforced c-Myb transcription can transform cells of lymphoid origin by stimulating cellular proliferation and inhibiting apoptotic pathways. Here we demonstrate that activation of the NF-κB pathway by the HTLV-1 Tax protein leads to transcriptional inactivation of c-Myb. This conclusion was supported by the fact that Tax mutants unable to stimulate the NF-κB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-κB activation by coexpression of IκBα restored c-Myb transcription, and Tax was unable to block c-Myb transcription in a NEMO knockout cell line. Importantly, physiological stimuli, such as signaling with the cellular cytokines tumor necrosis factor alpha, interleukin 1 beta (IL-1β), and lipopolysaccharide, also inhibited c-Myb transcription. These results uncover a new link between extracellular signaling and c-Myb-dependent transcription. The mechanism underlying NF-κB-mediated repression was identified as sequestration of the coactivators CBP/p300 by RelA. Interestingly, an amino-terminal deletion form of p300 lacking the C/H1 and KIX domains and unable to bind RelA retained the ability to stimulate c-Myb transcription and prevented NF-κB-mediated repression.

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health and in part from a fellowship to C. Nicot from La Ligue Nationale Contre le Cancer (Paris, France). RM was supported by a Bourse Roux from the Pasteur Institute.

We thank L. Wolff and T. Misteli for critical reading of the manuscript. We are indebted to L. Boxer, T. P. Bender, J. S. Lipsick, L. Wolff, C. Kitanaka, S. Ness, W. C. Greene, A. Israel, A. Baldwin, N. Rice, U. Siebenlist, D. Livingston, R. H. Goodman, V. Ogryzko, H. Nakatoni, A. Hoffmann, and D. Baltimore for generous gifts of reagents used in this study. S. Snodgrass provided editorial assistance.