Induction of Reactive Oxygen Species by Human T-Cell Leukemia Virus Type 1 Tax Correlates with DNA Damage and Expression of Cellular Senescence Marker

Kinjo, Takao; Ham-Terhune, Julia; Péloponèse, Jean-Marie; Jeang, Kuan‐Teh

doi:10.1128/jvi.02460-09

Cited by 71 publications

(71 citation statements)

References 39 publications

(43 reference statements)

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“…As activation of this pathway causes a fraction of Tax-expressing cells to halt cell cycle, 36 our data strengthen the link between Tax-induced enforced proliferation and DNA-damaging activities leading to cell-cycle arrest. Recent studies also suggest that DNA damage and H2AX phosphorylation in Tax-expressing cells result from induction of reactive oxygen species 9 and/or sequestration of DDR-associated proteins in TSS. [41][42][43] It thus appears that several Tax activities contribute to DSB formation and DDR pathway engagement.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Recent data also support a direct role for Tax-induced reactive oxygen species in the occurrence of DNA lesions. 9 Conceptually, Tax activities are achieved through proteinprotein interactions in both nuclear and cytoplasmic cellular compartments. 10 In the nucleus, Tax accumulates within foci called Tax speckled structures (TSS), 11 which overlap with the cellular machinery required for transcription, splicing, post-transcriptional modifications of proteins, DNA repair, and checkpoint control.…”

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confidence: 99%

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Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Boxus

Twizere

Legros

et al. 2012

Blood

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The Tax oncoprotein encoded by the human T-cell leukemia virus type 1 plays a pivotal role in viral persistence and pathogenesis. Human T-cell leukemia virus type 1-infected cells proliferate faster than normal lymphocytes, expand through mitotic division, and accumulate genomic lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7 helicase complex and localizes to origins of replication. Tax IntroductionHuman T-cell leukemia virus-1 (HTLV-1) is a retrovirus that infects approximately 20 million people worldwide. 1 Although the majority of infected people remain lifelong asymptomatic carriers, 2% to 5% develop either adult T-cell leukemia (ATL) or chronic inflammatory diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis. 1 Two major hallmarks of HTLV-1-infected cells are: preferential proliferation compared with normal lymphocytes 2 and tendency to accumulate genomic lesions, a prerequisite for oncogenesis. 3,4 Although the molecular mechanisms underlying T-cell transformation remain to be elucidated, it is generally accepted that the virally encoded Tax protein plays a central role. Tax indeed displays pleiotropic activities that cooperate to drive cell cycle progression and perturb genome stability. 4,5 For example, Tax shortens G 1 phase and accelerates transition into S phase by manipulating positive and negative G 1 phase regulators (ie, cyclin D/CDK complex, Rb and CDK inhibitors). [6][7][8] In addition, Tax is thought to indirectly generate DNA damage by suppressing DNA repair processes and competing with cellular DNA damage response (DDR). 4,5 Recent data also support a direct role for Tax-induced reactive oxygen species in the occurrence of DNA lesions. 9 Conceptually, Tax activities are achieved through proteinprotein interactions in both nuclear and cytoplasmic cellular compartments. 10 In the nucleus, Tax accumulates within foci called Tax speckled structures (TSS), 11 which overlap with the cellular machinery required for transcription, splicing, post-transcriptional modifications of proteins, DNA repair, and checkpoint control. 12 In this report, we further demonstrate that Tax recruits the MCM2-7 replicative helicase within the TSS and modulates the program of replication origin firing. Notably, this mechanism favors cell cycle progression and directly compromises genome stability. Methods Plasmids, antibodies, yeast 2-hybrid, and GST pulldownSee supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Cell cultureHeLa, Rat-1, and 293GP2 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and 2mM l-glutamine and penicillin/ streptomycin. Jurkat, HUT78 and JPX9 (Jurkat cell lines stably transfected either with tax-1 gene driven by a metallothionein-inducible promoter) were kept in RPMI 1640 supplemented with 10% FBS, 2mM l-glutamine, and penicillin/streptomycin. Expression of the viral protein was induced in JPX9 cells by adding 120 M zinc chloride...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Boxus

Twizere

Legros

et al. 2012

Blood

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“…within the host, but also subverts host cell DNA damage response mechanisms, cell cycle progression, and the apoptotic pathway (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

“…To date, there are no studies describing a role of exosomes in HTLV-1 infection. It has been shown that soluble Tax can be taken up by recipient cells, whereas soluble Tax treatment of uninfected cells induces TNF-␣ gene expression and enhances the proliferation of phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (18,53). Tax has been detected in the cerebrospinal fluid of HTLV-1-infected patients, in HAM/ TSP patients (54).…”

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confidence: 99%

Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein

Jaworski

Narayanan

Duyne

et al. 2014

Journal of Biological Chemistry

137

180

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Background: Extracellular exosomes contain various functional elements. Results: Exosomal Tax protein causes phenotypic changes in uninfected cells. Conclusion: Exosomes may play critical roles in extracellular delivery of oncogenic material derived from HTLV-1-infected cells. Significance: Exosomal delivery of Tax and other putative oncogenic components produced during HTLV-1 infection potentially contributes to pathogenesis of adult T-cell leukemia, myelopathy, or tropical spastic paraparesis.

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“…Blockade of transcription initiation and formation of SGs are known to belong to the complex cellular stress response that is triggered by DNA damage (Pothof et al, 2009a, b). Tax was recently shown to induce reactive oxygen species, change in the intracellular redox status and DNA damage through activation of both CREB and NF-kB (Kinjo et al, 2010). The M22 mutant (intact for CREB but defective for NF-kB activity) and the M47 mutant (intact for NF-kB but defective for CREB activity) used in this study retain their ability to induce the formation of SGs when expressed in the nucleus.…”

Section: Discussionmentioning

confidence: 92%

The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6

Legros

Boxus

Gatot³

et al. 2011

Oncogene

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Induction of Reactive Oxygen Species by Human T-Cell Leukemia Virus Type 1 Tax Correlates with DNA Damage and Expression of Cellular Senescence Marker

Cited by 71 publications

References 39 publications

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein

The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6

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