Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia

Wigdahl, Brian

doi:10.2741/a502

Cited by 6 publications

(2 citation statements)

References 84 publications

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“…Over a period of decades in vivo, a growth factor independent, monoclonal population of leukemic T cells emerges, likely as a consequence of the rapid growth of a single leukemic clone bearing multiple mutations in oncogenes and/or tumor suppressor genes (Yao and Wigdahl, 2000;Yoshida, 2001). The oncogenic potential of HTLV-1 resides in part in the viral Tax protein, a positive regulator of viral gene transcription which disrupts cell cycle control, gene transcription and signal transduction via proteinprotein interactions (Hiscott et al, 2001;Neuveut and Jeang, 2002;Yoshida, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…The ability of Tax to stimulate NFkB activity occurs via activation of the signaling cascade controlling IkB phosphorylation specifically through interaction with IKKg subunit of the IkB kinase complex (Chu et al, 1999;Sun et al, 2000;. These molecular events culminate in transcriptional dysregulation in HTLV-1 infected cells, leading to CD4+ T cell proliferation that predisposes to ATL development (Yao and Wigdahl, 2000;Yoshida, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

et al. 2002

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The human T cell leukemia/lymphotropic virus-1 (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes. Interferon regulatory factor-4 (IRF-4) was shown previously to be constitutively expressed in T cells infected with HTLV-1. In this study, we investigated the role of IRF-4 gene regulation in the context of HTLV-1 infection using gene array technology and IRF-4 expressing T cells. Many potential IRF-4 regulated genes were identified, the vast majority of which were repressed by IRF-4 expression. Cyclin B1, a G2-M checkpoint protein identified as an IRF-4 repressed gene in the array, was further characterized in the context of HTLV-1 infection. All HTLV-1 infected cell lines and ATL patient lymphocytes demonstrated a dramatic decrease in cyclin B1 levels; subsequent analysis of the cyclin B1 promoter identified two sites important in IRF-4 binding and repression of cyclin B1 expression. Furthermore, IRF-4-mediated repression of cyclin B1 led to a significant decrease in CDC2 kinase activity in HTLV-1 infected T cells. IRF-4 expression in HTLV-1 infected T cells also downregulated other genes implicated in the mitotic checkpoint as well as genes involved in actin cytoskeletal rearrangement, DNA repair, apoptosis, metastasis and immune recognition. Several of the identified genes are dysregulated in ATL and may provide important mechanistic information concerning pathways critical to the emergence of ATL.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

et al. 2002

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Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-κB activation

et al. 2001

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The Tax protein of human T-lymphotropic virus type 1 (HTLV-1), an oncoprotein that transactivates viral and cellular genes, plays a key role in HTLV-1 replication and pathogenesis. We used cDNA microarrays to examine Tax-mediated transcriptional changes in the human Jurkat T-cell lines JPX-9 and JPX-M which express Tax and Tax-mutant protein, respectively, under the control of an inducible promoter. Approximately 300 of the over 2000 genes examined were di erentially expressed in the presence of Tax. These genes were grouped according to their function and are discussed in the context of existing ®ndings in the literature. There was strong agreement between our results and genes previously reported as being Tax-responsive. Genes that were di erentially expressed in the presence of Tax included those related to apoptosis, the cell cycle and DNA repair, signaling factors, immune modulators, cytokines and growth factors, and adhesion molecules. Functionally, we provide evidence that one of these genes, the mixed-lineage kinase MLK-3, is involved in Tax-mediated NF-kB signaling. Our current results provide additional insights into Tax-mediated signaling. Oncogene (2001) 20, 4484 ± 4496.

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The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB Activation

Shembade

Harhaj

Yamamoto

et al. 2007

J Virol

105

138

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Ubiquitination of the human T-cell leukemia virus 1 Tax oncoprotein provides an important regulatory mechanism that promotes the Tax-mediated activation of NF-B. However, the type of polyubiquitin chain linkages and the host factors that are required for Tax ubiquitination have not been identified. Here, we demonstrate that Tax polyubiquitin chains are composed predominantly of lysine 63-linked chains. Furthermore, the ubiquitination of Tax is critically dependent on the E2 ubiquitin-conjugating enzyme Ubc13. Tax interacts with Ubc13, and small interfering RNA-mediated knockdown of Ubc13 expression abrogates Tax ubiquitination and the activation of NF-B. Mouse fibroblasts lacking Ubc13 exhibit impaired Tax activation of NF-B despite normal tumor necrosis factor-and interleukin-1-mediated NF-B activation. Finally, the interaction of Tax with NEMO is disrupted in the absence of Tax ubiquitination and Ubc13 expression, suggesting that Tax ubiquitination is critical for NEMO binding. Collectively, our results reveal that Ubc13 is essential for Tax ubiquitination, its interaction with NEMO, and Tax-mediated NF-B activation.

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Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia

Cited by 6 publications

References 84 publications

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-κB activation

The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB Activation

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