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