Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Matteucci, Claudia; Balestrieri, Emanuela; Macchi, Beatrice; Mastino, Antonio

doi:10.1002/jmv.20201

Cited by 6 publications

(3 citation statements)

References 27 publications

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“…However, doses Ͻ6.0 M proved to be highly specific for PKC inhibition and kept the viability of PBLs and Jurkat mostly at basal levels. Furthermore, MT-2 cells were surprisingly resilient to rottlerin-induced apoptosis (Ͼ100 M), probably due to the concomitant infection with HTLV-1, which appears to suppress apoptosis as a mechanism involved in the immortalization of the infected lymphocytes (61,62). In fact, although MT-2 cells are usually destroyed by pGeneClip-iPKC-C1 and pGeneClip vectors were used as negative controls.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

López-Huertas

Mateos

Dı́az-Gil

et al. 2011

Journal of Biological Chemistry

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The novel protein serine/threonine kinase C (PKC) isoform is selectively expressed in T lymphocytes but not B lymphocytes, erythrocytes, polymorphonuclear neutrophils, monocytes, or macrophages (1). Other PKC isotypes (␣, ␤, ␦, ⑀, , and ) are also expressed in T cells, but PKC is essential for T cell receptor/CD3-mediated activation events (2, 3). Among novel PKCs, PKC displays the highest amino acid similarity with PKC␦, not only in the catalytic or kinase core and the diacylglycerol binding regulatory domain C1 but mainly in the NH 2 -terminal V1 domain (2). However, V3 domain of PKC is unique and does not show significant similarity with any other PKC isoforms, including PKC␦. As a result, PKC provides a molecular basis for isotype selectivity and the non-redundant activity of distinct PKC isoenzymes in T cells (4).PKC kinase activity is regulated by phosphorylation of the activation-loop residue Thr 538 on the catalytic domain during T cell activation (5). Residue Thr 538 has been described as critical for PKC catalytic activity for regulating phosphorylation of the hydrophobic motif and for enabling CD3-mediated nuclear factor-B (NF-B) activation (6). PKC also shows the unique property of being translocated to the plasma membrane lipid rafts during the immunological synapse between T cells and antigen-presenting cells (7-9). Recruitment of PKC to the immunological synapse induces the activation of intracellular signaling pathways as the mitogen-activated protein kinase and the NF-B pathway (10), essential for the regulation of T cell growth-promoting genes as IL-2 (interleukin-2) (3, 11). NF-B is also critical for the replication of the human immunodeficiency virus type 1 (HIV-1) in human blood CD4 ϩ T cells (12). The main NF-B inhibitor, IB␣, binds to the NF-B nuclear localization signal to keep it inactive in the cytoplasm in the absence of activation. Upon T cell activation, IB␣ is phosphorylated by the IB kinase complex and degraded in the proteasome (13), releasing the nuclear localization signal and allowing NF-B translocation to the nucleus, where binds to cognate sequences in inducible gene promoters (14), as the HIV-1 long terminal promoter (LTR).The main target for HIV-1 infection is the CD4 ϩ T cell population, in particular memory CD4 ϩ T cells that are generated by antigen recognition (15). The viral genome can be permanently integrated in the chromosomes of these cells, producing latent reservoirs with long half-life. HIV-1-infected memory T cells remain undetectable by the immune system and the highly active antiretroviral therapy (HAART) 4 when they are in a resting state, but they are able to release new batches of virions after

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Section: Discussionmentioning

confidence: 99%

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

López-Huertas

Mateos

Dı́az-Gil

et al. 2011

Journal of Biological Chemistry

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“…As observed in other neoplasia, the balance between pro and anti apoptotic response is subverted in ATL cells. Preclinical studies have shown that HTLV-1 infection in vitro gives rise, in a first phase, to high proliferation and a concomitant high apoptosis rate in infected cells until, in a successive phase, the selection of immortalized clones lead to outgrowth of cells preferentially exhibiting anti-apoptotic gene expression ( Matteucci et al, 2004 ). Coherently, transformed clones from ATL patients over-express in culture the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w proteins and exhibit ex vivo a 10- to 20-fold higher sensitivity to navitoclax (ABT-263), an orally bio-available mimetic of the Bcl-2 homology domain 3 small molecule, as compared to non-HTLV-1-associated leukemic cells ( Tse et al, 2008 ).…”

Section: Targeted Biological Therapy For Atlmentioning

confidence: 99%

Future Perspectives on Drug Targeting in Adult T Cell Leukemia-Lymphoma

et al. 2018

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Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia/lymphoma (ATL), HTLV-1 associated myelopathy (HAM/TSP), and of a number of inflammatory diseases with an estimated 10–20 million infected individuals worldwide. Despite a number of therapeutic approaches, a cure for ATL is still in its infancy. Conventional chemotherapy has short-term efficacy, particularly in the acute subtype. Allogeneic stem cell transplantation offers long-term disease control to around one third of transplanted patients, but few can reach to transplant. This prompted, over the past recent years, the conduction of a number of clinical trials using novel treatments. Meanwhile, new data have been accumulated on biological and molecular bases of HTLV-1 transforming and infecting activity. These data offer new rational for targeted therapies of ATL. Taking into account the double-face of ATL as an hematologic malignancy as well as a viral infectious disease, this Mini-Review seeks to provide an up-to-date overview of recent efforts in the understanding of the mechanisms involved in already used therapeutic regimens showing promising results, and in selecting novel drug targets for ATL.

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“…The prevalence of HTLV-1 infection for the general population in certain areas of Iran such as Mashhad and Sabzevar is estimated to be 2.12 % and 1.6%, respectively and in Neyshabour this is 7.2% for the referred population (4)(5)(6)(7). Approximately 5% of the estimated 20 million HTLV-1-infected individuals are at risk of eventually developing HTLV-1-associated diseases (8) such as adult T-cell lymphoma/leukemia (ATL or ATLL ), a fatal disease with Median Survival Time (MST) of less than 1 year (9) and chronic progressive disorder, HTLV-I Associated myelopathy/tropical spastic paraparesis (HAM/TSP) (10).…”

Section: Introductionmentioning

confidence: 99%

Examination of a Reporter Vector for HTLV-1 Infectivity Using MT2, a HTLV-1 Producer Cell Line

Abdizadeh

Makvandi

Samarbafzadeh

et al. 2013

Jundishapur J Microbiol

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Background: HTLV-1 (Human T_cell lymphotropic virus type 1), with about 20 million individuals infected worldwide, is a global health problem that is endemic in certain areas such as Japan and Khorasan province of Iran.HTLV-1 is the causative agent of progressive diseases, Adult T cell Leukemia (ATL), and HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), which do not yet have approved effective treatment. Due to the non-cytolytic characteristic of this virus and cell associated properties, there is no routine Procedure for drug study in vitro and it's confined to some HTLV infected cell lines. Therefore construction of a reporter vector is necessary to evaluate HTLV-1 infectivity in cell culture for drug studies, since designed reporters for retroviruses are usually based on long terminal repeat (LTR) transactivation. LTR region of HTLV-1 contains a virus promoter that plays the most important role in replication and transcription by the Tax transactivation effect. Objectives: In this project we attempted to construct a reporter vector containing the luciferase gene coupled to the HTLV-1 promoter for evaluation of HTLV-1 infectivity. Material and Methods: LTR region was digested from pUCLTR-Lac by HindIII and sub-cloned into the Multiple cloning site (MCS) region of a promoter-less reporter vector, pGL4.17, upstream to the luciferase gene. Colonies were screened by Colony PCR, then selected colonies were confirmed by restriction enzyme digestion and sequencing. Human embryonic kidney (HEK) 293T cell line was transfected by a recombinant vector and inducible expression of luciferase was evaluated. Results: Recombinant vector, pGL4LTR-Luc, has expression levels of more than 50 folds compared to the control when co-transfected with the Tax expressing vector into HEK 293T cells. Moreover, cells display more than 30 folds of luciferase expression over 2 days when cocultured with MT2 cell, a HTLV-1 producer cell line. Conclusions: According to the high functionality of the produced recombinant vector, it seems a good applicable tool for making an indicator cell line in subsequent basic and drug studies.

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Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Cited by 6 publications

References 27 publications

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

Future Perspectives on Drug Targeting in Adult T Cell Leukemia-Lymphoma

Examination of a Reporter Vector for HTLV-1 Infectivity Using MT2, a HTLV-1 Producer Cell Line

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