Article

Enhanced activation of tax-dependent transcription of human T-cell leukemia virus type I (HTLV-I) long terminal repeat by TORC3

Institute for Virus Research, Kyoto University, Kioto, Kyōto, Japan
Journal of Biological Chemistry (Impact Factor: 4.6). 01/2005; 279(51):52978-83. DOI: 10.1074/jbc.M409021200
Source: PubMed

ABSTRACT Tax, a protein encoded by the env-pX gene of human T-cell leukemia virus type I (HTLV-I), interacts with various host cell transcription factors. Tax activates transcription from the long terminal repeat (LTR) of HTLV-I through association with cyclic AMP-responsive element-binding protein (CREB). Here, we present evidence that transducer of regulated cyclic AMP-response element-binding protein 3 (TORC3), a co-activator of CREB, is involved in Tax-induced transcriptional activation from the HTLV-I LTR. By using a luciferase assay system, we show that TORC3 alone can enhance transcription from the HTLV-I LTR, as well as from a cellular cyclic AMP-response element (CRE). Interestingly, we find that co-expression of TORC3 and Tax dramatically increased transcriptional activation at the HTLV-I LTR. We also show by glutathione S-transferase pull-down and co-immunoprecipitation experiments that TORC3 interacts with Tax. Using deletion mutant analysis, we identify the Tax interaction domain of TORC3 as a region spanning from amino acid 1 to 103, which contains a coiled-coil domain. These results provide important clues toward understanding the molecular mechanism of Tax-dependent transcriptional activation of the HTLV-I LTR.

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    • "TORCs enhance the interaction of CREB with the TFII130 component of Transcription factor II D (TFIID) thus enhancing the transcriptional initiation potential of CREB (Koga et al., 2004; Siu et al., 2006). These proteins can also interact with Tax to enhance HTLV-1 transcription (Koga et al., 2004; Siu et al., 2006; Nyborg et al., 2010). The work of Jiang and coworkers has proposed an interesting potential role for TORC2 in HTLV-1 infections. "
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    ABSTRACT: Human T-cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2-5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator, and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent body of literature that refines our understanding of cellular transformation. A focused range of topics are discussed in this review including Tax-mediated regulation of the viral promoter and other cellular pathways, particularly the connection of the NF-κB pathway to both post-translational modifications (PTMs) of Tax and subcellular localization. Specifically, recent research on polyubiquitination of Tax as it relates to the activation of the IkappaB kinase (IKK) complex is highlighted. Regulation of the cell cycle and DNA damage responses due to Tax are also discussed, including Tax interaction with minichromosome maintenance proteins and the role of Tax in chromatin remodeling. The recent identification of HTLV-3 has amplified the importance of the characterization of emerging viral pathogens. The challenge of the molecular determination of pathogenicity and malignant disease of this virus lies in the comparison of the viral transactivators of HTLV-1, -2, and -3 in terms of transformation and immortalization. Consequently, differences between the three proteins are currently being studied to determine what factors are required for the differences in tumorogenesis.
    Frontiers in Microbiology 11/2012; 3:406. DOI:10.3389/fmicb.2012.00406 · 3.94 Impact Factor
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    • "These findings indicate that Tax and TORC2 cooperate to activate expression of the cyclin D1 gene. This result is consistent with the previously reported activation of a generic cellular CRE reporter plasmid by Tax and TORC3 (Koga et al., 2004). However, the molecular basis for the observed functional cooperativity between Tax and the TORC proteins is unknown. "
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    ABSTRACT: Adult T-cell leukemia/lymphoma is a fatal malignancy etiologically linked to infection with the human T-cell leukemia virus (HTLV-1). The virally encoded oncoprotein Tax activates the transcription of HTLV-1 and cellular genes by cooperating with cellular transcription factors. Cyclin D1 is a pivotal regulator of cell cycle progression, and increased expression strongly correlates with malignant transformation. Here, we characterize the mechanism of Tax transactivation of cyclin D1. We find that cyclin D1 transcript levels are elevated in HTLV-1 infected cells and that Tax physically associates with the cyclin D1 gene in vivo. Tax binds the cyclin D1 promoter-proximal cyclic AMP response element (CRE) in the presence of phosphorylated CREB (pCREB) in vitro, and together the Tax-pCREB complex recruits the cellular co-activator p300 to the promoter through this unconventional Tax-responsive element. We further show that the transducer of regulated CREB 2 (TORC2) cooperates with Tax to further enhance p300 recruitment to the cyclin D1 promoter in vitro. Tax and TORC2 in combination stimulate cyclin D1 expression in vivo, demonstrating the functional outcome of the binding interactions. Together, our findings support a model in which Tax-induced accumulation of cyclin D1 shortens the G1 phase of the cell cycle, promotes mitotic replication of the virus, and drives selection and expansion of malignant T-cells.
    Oncogene 04/2010; 29(14):2142-52. DOI:10.1038/onc.2009.498 · 8.56 Impact Factor
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    • "Tax, an oncogenic viral protein of HTLV-I, physically interacts with CREB to potentiate CREB dimerization and DNA binding to allow for the recruitment of the coactivators p300 and CBP in the absence of serine- 133 phosphorylation [25]. Tax has also been shown to bind TORCs to potentiate CREB activation and increase the transcription of viral and cellular targets of CREB [26] [27]. Another oncogenic retrovirus, Hepatitis B virus (HBV), has also been shown to promote cellular transformation by enhancing CREB target gene expression in a similar way to HTLV-1. "
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    ABSTRACT: The cAMP response element-binding protein (CREB) is a nuclear transcription factor downstream of cell surface receptors and mitogens that is critical for normal and neoplastic hematopoiesis. Previous work from our laboratory demonstrated that a majority of patients with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) overexpress CREB in the bone marrow. To understand the role of CREB in leukemogenesis, we examined the biological effect of CREB overexpression on primary leukemia cells, leukemia cell lines, and CREB overexpressing transgenic mice. Our results demonstrated that CREB overexpression leads to an increase in cellular proliferation and survival. Furthermore, CREB transgenic mice develop a myeloproliferative disorder with aberrant myelopoiesis in both the bone marrow and spleen. Additional research from other groups has shown that the expression of the cAMP early inducible repressor (ICER), a CREB repressor, is also deregulated in leukemias. And, miR-34b, a microRNA that negative regulates CREB expression, is expressed at lower levels in myeloid leukemia cell lines compared to that of healthy bone marrow. Taken together, these data suggest that CREB plays a role in cellular transformation. The data also suggest that CREB-specific signaling pathways could possibly serve as potential targets for therapeutic intervention.
    Advances in Hematology 08/2009; 2009:634292. DOI:10.1155/2009/634292
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