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Molecular and Cellular Biology, November 2001, p. 7391-7402, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7391-7402.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Christophe Nicot,1,* Renaud Mahieux,2 Cynthia Pise-Masison,3 John Brady,3 Antoine Gessain,2 Shoji Yamaoka,4 and Genoveffa Franchini1

Section of Animal Models and Retroviral Vaccines1 and Section of Virus and Tumor Biology,3 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Unite d'Epidemiologie et Physiopathologie des Virus Oncogenes, Institut Pasteur, 75724 Paris cedex 15, France2; and Department of Microbiology, Tokyo Medical and Dental University, Bunkyo-ku, 113-8519 Tokyo, Japan4

Received 25 June 2001/Returned for modification 6 August 2001/Accepted 10 August 2001

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-kappa B 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-kappa B pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-kappa B activation by coexpression of Ikappa Balpha 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-1beta ), 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-kappa B-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-kappa B-mediated repression.

* Corresponding author. Mailing address: NCI Ctr. for Cancer Research BRL, Section of Animal Models and Retroviral Vaccines, 41 Library Dr., Bldg. 41, Room C303, Bethesda, MD 20892. Phone: (301) 402-0303. Fax: (301) 402-0055. E-mail: cbeben{at}helix.nih.gov.

Molecular and Cellular Biology, November 2001, p. 7391-7402, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7391-7402.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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