Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling

Twizere, Jean-Claude; Springael, Jean–Yves; Boxus, Mathieu; Burny, Arsène; Dequiedt, Samuel; Dewulf, Jean-François; Duchateau, Julie; Portetelle, Daniel; Urbain, Patrice; Lint, Carine Van; Green, Patrick L.; Mahieux, Renaud; Parmentier, Marc; Willems, Lucas; Kettmann, Richard

doi:10.1182/blood-2006-06-026781

Cited by 25 publications

(26 citation statements)

References 82 publications

(89 reference statements)

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“…To conclude, HTLV-1 infection has the ability to influence the CRMP2/PI3K/Akt/GSK-3 axis in T lymphocyte thus to positively control the migratory activity of infected cells. The present observation on ex vivo lymphocytes complements two previous reports showing that HTLV-1 regulates G protein signaling, in particular, activates the SDF1/CXCR4 axis in T lymphocyte of ATL patients, lymphoblastoid cells from Tax transgenic mice, and HTLV-1-infected T cell lines (75,76).…”

Section: Discussionsupporting

confidence: 90%

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Varrin‐Doyer

Nicolle

Marignier

et al. 2012

The Journal of Immunology

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Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1–induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69+ cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1–infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation.

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Section: Discussionsupporting

confidence: 90%

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Varrin‐Doyer

Nicolle

Marignier

et al. 2012

The Journal of Immunology

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“…In addition, expression of the HTLV-I regulatory protein Tax in immortalized T-cell lines has been shown to be involved the activation of the SDF-1␣/CXCR4 pathway. 29 The present study has clearly demonstrated the cell surface expression of CXCR4 on leukemic cells, a specific chemotactic response to SDF-1␣, and that cell migration is associated with MEK-ERK signaling. Following the interaction with SDF-1␣, surface CXCR4 translocates to an intracellular compartment.…”

Section: Discussionsupporting

confidence: 62%

Inhibition of the SDF-1α–CXCR4 axis by the CXCR4 antagonist AMD3100 suppresses the migration of cultured cells from ATL patients and murine lymphoblastoid cells from HTLV-I Tax transgenic mice

Kawaguchi

Orba

Kimura

et al. 2009

Blood

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“…Current data support the view that the viral Tax protein is instrumental for oncogenesis, as has been demonstrated in in vitro transformation assays and animal models [3]. The Tax protein affects multiple intracellular processes and signaling pathways, including cell cycle progression, cell survival, mitosis, and genomic stability [4–6]. Surprisingly, however, tax transcripts are detected in only 40% of all primary ATLL tumors [7,8], further pointing to the complexity of the HTLV-1 induced transformation and oncogenesis process, the mechanisms of which remain to be elucidated.…”

Section: Introductionmentioning

confidence: 57%

Expression profiles of adult T-cell leukemia–lymphoma and associations with clinical responses to zidovudine and interferon α

Alizadeh

Bohen

Lossos

et al. 2010

Leukemia & Lymphoma

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Adult T-cell leukemia–lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon α (IFNα). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT–IFNα therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT–IFNα differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT–IFNα therapy may provide novel insights into the mechanisms of action in ATLL.

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Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling

Cited by 25 publications

References 82 publications

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Inhibition of the SDF-1α–CXCR4 axis by the CXCR4 antagonist AMD3100 suppresses the migration of cultured cells from ATL patients and murine lymphoblastoid cells from HTLV-I Tax transgenic mice

Expression profiles of adult T-cell leukemia–lymphoma and associations with clinical responses to zidovudine and interferon α

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