Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4)

Reddy, T. Raghunadha; Tang, Hengli; Li, Xinqiang; Wong‐Staal, Flossie

doi:10.1038/sj.onc.1201119

Cited by 74 publications

(79 citation statements)

References 18 publications

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“…Analysis of the nuclear lysates demonstrated an increase in PKR levels only with VVeq904 infection. Immunoblotting for actin demonstrated comparable protein loading, while the degree of cross-contamination between the cytoplasmic and nuclear samples was minimal as determined by analysis of the distribution of the cytoplasmic marker superoxide dismutase 4 (70) and the nuclear protein ATF4 (58).…”

Section: Resultsmentioning

confidence: 99%

Binding and Nuclear Relocalization of Protein Kinase R by Human Cytomegalovirus TRS1

Hakki

Marshall²,

Niro³

et al. 2006

J Virol

104

100

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The human cytomegalovirus (HCMV) TRS1 and IRS1 genes block the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2␣) and the consequent shutoff of cellular protein synthesis that occur during infection with vaccinia virus (VV) deleted of the double-stranded RNA binding protein gene E3L (VV⌬E3L). To further define the underlying mechanism, we first evaluated the effect of pTRS1 on protein kinase R (PKR), the double-stranded RNA (dsRNA)-dependent eIF2␣ kinase. Immunoblot analyses revealed that pTRS1 expression in the context of a VV⌬E3L recombinant decreased levels of PKR in the cytoplasm and increased its levels in the nucleus of infected cells, an effect not seen with wild-type VV or a VV⌬E3L recombinant virus expressing E3L. This effect of pTRS1 was confirmed by visualizing the nuclear relocalization of PKR-EGFP expressed by transient transfection. PKR present in both the nuclear and cytoplasmic fractions was nonphosphorylated, indicating that it was unactivated when TRS1 was present. PKR also accumulated in the nucleus during HCMV infection as determined by indirect immunofluorescence and immunoblot analysis. Binding assays revealed that pTRS1 interacted with PKR in mammalian cells and in vitro. This interaction required the same carboxy-terminal region of pTRS1 that is necessary to rescue VV⌬E3L replication in HeLa cells. The carboxy terminus of pIRS1 was also required for rescue of VV⌬E3L and for mediating an interaction of pIRS1 with PKR. These results suggest that these HCMV genes directly interact with PKR and inhibit its activation by sequestering it in the nucleus, away from both its activator, cytoplasmic dsRNA, and its substrate, eIF2␣.Double-stranded RNA (dsRNA) activates the host cell response to viral infection in numerous ways, one of which involves the interferon-induced, dsRNA-dependent protein kinase R (PKR) (reviewed in reference 43). After binding to dsRNA, PKR dimerizes, autophosphorylates, and then phosphorylates the eukaryotic initiation factor 2 (eIF2) on its ␣ subunit. Phosphorylated eIF2␣ sequesters the guanine nucleotide exchange factor eIF2B, resulting in the inhibition of protein synthesis at the level of translation initiation. Since viruses depend on the cellular translational machinery, the shutoff of host cell protein synthesis inhibits viral replication and spread.Many viruses have mechanisms for inhibiting the PKR-mediated phosphorylation of eIF2␣ (56). The vaccinia virus (VV) E3L protein prevents the activation of PKR by binding to and sequestering dsRNA via a carboxy-terminal double-stranded RNA binding domain (dsRBD) (39). VV from which the E3L gene has been deleted (VV⌬E3L) exhibits a dsRNA-dependent restriction of host cell range, and this phenotype can be reversed by expression of the dsRBD from pE3L or dsRNAbinding proteins from other viruses (4, 47, 62). We previously found that the products of the human cytomegalovirus (HCMV) genes TRS1 and IRS1 restore the host cell range of VV⌬E3L, inhibit the phosphorylation of eIF2␣, and prevent the shutoff...

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Section: Resultsmentioning

confidence: 99%

Binding and Nuclear Relocalization of Protein Kinase R by Human Cytomegalovirus TRS1

Hakki

Marshall²,

Niro³

et al. 2006

J Virol

104

100

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“…HTLV-I basal transcription is greatly enhanced by the virus-encoded regulatory protein Tax, which mediates trans-activation of the HTLV-I LTR by interacting with cellular transcription factors that bind to the three 21 bp repeats within TRE-1, in addition to TRE-2 (Nyborg et al, 1988;Bosselut et al, 1990Bosselut et al, , 1992Nyborg and Dynan, 1990;Muchardt et al, 1992;Zhao and Giam, 1992;Clark et al, 1993;Franklin et al, 1993;Baranger et al, 1995;Brauweiler et al, 1995;Fujii et al, 1995;Barnhart et al, 1997;Lenzmeier and Nyborg, 1997;Reddy et al, 1997;Yan et al, 1998;Goren et al, 1999;Van Orden et al, 1999;Mick et al, 2000;Scoggin et al, 2001). Initially, it was thought that Tax did not interact directly with Tax-responsive sequences within the LTR, but instead trans-activated viral transcription by interacting with cellular transcription factors that directly interact with the TREs (Baranger et al, 1995;Perini et al, 1995;Giebler et al, 1997).…”

Section: Cellular Mechanisms Regulating Htlv-i Viral Gene Expressionmentioning

confidence: 99%

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

Grant

Barmak

Alefantis

et al. 2002

Journal Cellular Physiology

101

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Human T cell lymphotropic/leukemia virus type I (HTLV‐I) has been identified as the causative agent of both adult T cell leukemia (ATL) and HTLV‐I‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the exact sequence of events that occur during the early stages of infection are not known in detail, the initial route of infection may predetermine, along with host, environmental, and viral factors, the subset of target cells and/or the primary immune response encountered by HTLV‐I, and whether an HTLV‐I‐infected individual will remain asymptomatic, develop ATL, or progress to the neuroinflammatory disease, HAM/TSP. Although a large number of studies have indicated that CD4+ T cells represent an important target for HTLV‐I infection in the peripheral blood (PB), additional evidence has accumulated over the past several years demonstrating that HTLV‐I can infect several additional cellular compartments in vivo, including CD8+ T lymphocytes, PB monocytes, dendritic cells, B lymphocytes, and resident central nervous system (CNS) astrocytes. More importantly, extensive latent viral infection of the bone marrow, including cells likely to be hematopoietic progenitor cells, has been observed in individuals with HAM/TSP as well as some asymptomatic carriers, but to a much lesser extent in individuals with ATL. Furthermore, HTLV‐I+ CD34+ hematopoietic progenitor cells can maintain the intact proviral genome and initiate viral gene expression during the differentiation process. Introduction of HTLV‐I‐infected bone marrow progenitor cells into the PB, followed by genomic activation and low level viral gene expression may lead to an increase in proviral DNA load in the PB, resulting in a progressive state of immune dysregulation including the generation of a detrimental cytotoxic Tax‐specific CD8+ T cell population, anti‐HTLV‐I antibodies, and neurotoxic cytokines involved in disruption of myelin‐producing cells and neuronal degradation characteristic of HAM/TSP. J. Cell. Physiol. 190: 133–159, 2002. © 2002 Wiley‐Liss, Inc.

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“…The transcriptional selectivity of ATF4 is modulated by the formation of heterodimers with multiple C/EBP bZIP proteins including: CHOP/ GADD153 (Gachon et al, 2001), C/EBPa (Nishizawa and Nagata, 1992), C/EBPb, CRP2 (Vallejo et al, 1993), and C/EBPg (Vinson et al, 1993) as well as AP-1 family members (fos and jun proteins) (Hai and Curran, 1991;Kato et al, 1999). ATF4 also associates with Tax, a human T-cell leukemia virus type I transactivator (Reddy et al, 1997), CREB-binding protein (CBP) (Liang and Hai, 1997), and Zip kinase (Kawai et al, 1998). Additionally, protein stability plays a role in modulating ATF4 function.…”

Section: Introductionmentioning

confidence: 99%

SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia

2003

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Regions of hypoxia are a hallmark of solid tumors. Tumor cells modulate the regulation of specific genes allowing adaptation and survival in the harsh hypoxic environment. We have identified SKIP3, a novel human kinase-like gene, which is overexpressed in multiple human tumors and is regulated by hypoxia. SKIP3 is an ortholog of the Drosophila tribbles, rat NIPK, dog C5FW, and human C8FW genes. Drosophila tribbles is involved in slowing cell-cycle progression during Drosophila development, but little is known regarding the function or tissue distribution of the vertebrate orthologs. We show that the normal tissue expression of SKIP3 is confined to human liver, while multiple primary human lung, colon, and breast tumors express high levels of SKIP3 transcript. Endogenous SKIP3 protein accumulates within 48 h under hypoxic growth conditions in HT-29 and PC-3 cells, with upregulation of the SKIP3 mRNA transcript by 72 h. We identified activating transcription factor 4 (ATF4) as a SKIP3-binding partner using the yeast-two-hybrid assay. Coexpression of SKIP3 and ATF4 showed that SKIP3 is associated with the proteolysis of ATF4, which can be blocked using a proteosome inhibitor. These results indicate that SKIP3 may be an important participant in tumor cell growth.

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Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4)

Cited by 74 publications

References 18 publications

Binding and Nuclear Relocalization of Protein Kinase R by Human Cytomegalovirus TRS1

Binding and Nuclear Relocalization of Protein Kinase R by Human Cytomegalovirus TRS1

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia

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