Human T-cell Lymphotropic Virus Type 1 Tax Represses C-Myb-dependent Transcription Through Activation of the NF-kappaB Pathway and Modulation of Coactivator Usage

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2001 Oct 5

PMID 11585920

Citations 15

Authors

C Nicot

R Mahieux

C Pise-Masison

J Brady

A Gessain

S Yamaoka

G Franchini

Affiliations

Soon will be listed here.

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-kappaB 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-kappaB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-kappaB activation by coexpression of IkappaBalpha 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-kappaB-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-kappaB-mediated repression.

Citing Articles

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Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression.

Kasper L, Fukuyama T, Lerach S, Chang Y, Xu W, Wu S PLoS One. 2013; 8(12):e82684.

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HTLV-I tax increases genetic instability by inducing DNA double strand breaks during DNA replication and switching repair to NHEJ.

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HTLV-I Tax regulates the cellular proliferation through the down-regulation of PIP3-phosphatase expressions via the NF-κB pathway.

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