Kaposi's Sarcoma-Associated Herpesvirus vFLIP and Human T Cell Lymphotropic Virus Type 1 Tax Oncogenic Proteins Activate IκB Kinase Subunit γ by Different Mechanisms Independent of the Physiological Cytokine-Induced Pathways

Shimizu, Akira; Baratchian, Mehdi; Takeuchi, Yasu; Escors, David; MacDonald, Douglas; Barrett, Tracey E.; Bagnéris, Claire; Collins, Mary; Noursadeghi, Mahdad

doi:10.1128/jvi.02337-10

Cited by 15 publications

(16 citation statements)

References 21 publications

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“…A similar strategy was applied using lentiviral vectors (lentivectors) by the expression of Kaposi's sarcoma herpesvirus vFLIP protein. vFLIP is a constitutive activator of the NF-B pathway, and its activities are associated to cell transformation and oncogenesis [213][214][215]. Interestingly, its expression in DCs using lentivectors resulted in their phenotypic maturation and production of proinflammatory cytokines, similarly to NIK overexpression using adenoviral vectors [216].…”

Section: Constitutive Activation Of Intracellular Signalling Pathwaysmentioning

confidence: 99%

Tumour Immunogenicity, Antigen Presentation, and Immunological Barriers in Cancer Immunotherapy

Escors

2014

New Journal of Science

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Since the beginning of the 20th century, scientists have tried to stimulate the antitumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical antineoplastic treatments such as surgery, radiotherapy, and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anticancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review, we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy.

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Section: Constitutive Activation Of Intracellular Signalling Pathwaysmentioning

confidence: 99%

Tumour Immunogenicity, Antigen Presentation, and Immunological Barriers in Cancer Immunotherapy

Escors

2014

New Journal of Science

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“…This system showed that IKK could not be directly activated by Tax, however was activated by MEKK1, and also suggested that Tax-K63-linked polyubiquitination is necessary for Tax-induced IKK activation (Shibata et al, 2011). Another study suggested that Tax can bind directly to IKKγ and activate IKK independent of the signaling pathways physiologically induced by cytokines (Shimizu et al, 2011). Tax activates the non-canonical pathway by directly inducing the processing of p100 to p52 through the recruitment of a IKKγ/IKK complex containing only IKKα, which both activates and recruits IKKα onto the p100 complex.…”

Section: Tax-mediated Activation Of the Nf-κb Pathway Is Vital For Htmentioning

confidence: 99%

HTLV Tax: A Fascinating Multifunctional Co-Regulator of Viral and Cellular Pathways

Currer¹,

Duyne²,

Jaworski³

et al. 2012

Front. Microbio.

122

133

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Human T-cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2–5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator, and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent body of literature that refines our understanding of cellular transformation. A focused range of topics are discussed in this review including Tax-mediated regulation of the viral promoter and other cellular pathways, particularly the connection of the NF-κB pathway to both post-translational modifications (PTMs) of Tax and subcellular localization. Specifically, recent research on polyubiquitination of Tax as it relates to the activation of the IkappaB kinase (IKK) complex is highlighted. Regulation of the cell cycle and DNA damage responses due to Tax are also discussed, including Tax interaction with minichromosome maintenance proteins and the role of Tax in chromatin remodeling. The recent identification of HTLV-3 has amplified the importance of the characterization of emerging viral pathogens. The challenge of the molecular determination of pathogenicity and malignant disease of this virus lies in the comparison of the viral transactivators of HTLV-1, -2, and -3 in terms of transformation and immortalization. Consequently, differences between the three proteins are currently being studied to determine what factors are required for the differences in tumorogenesis.

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“…he NF-κB essential modulator (NEMO or IKKγ) serves as a key fulcrum in the NF-κB pathway by relaying upstream signals to the IKK complex catalytic subunits through its elongated coiled coil motif 1 . NEMO is hijacked by various external factors, including viral oncoproteins [2][3][4] to initiate aberrant signaling; however, the topological complexity of the NEMO-mediated protein-protein interactions (PPIs) has limited discovery of inhibitors. The challenge of disrupting intracellular tertiary structure mediated protein-protein interactions is wellappreciated [5][6][7] .…”

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confidence: 99%

Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics

et al. 2020

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Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-κB signaling, exemplify this challenge. Various regulators are known to interact with different coiled coil regions of NEMO, but the topological complexity of this protein has limited inhibitor design. We undertook a comprehensive effort to block the interaction between vFLIP, a Kaposi's sarcoma herpesviral oncoprotein, and NEMO using small molecule screening and rational design. Our efforts reveal that a tertiary protein structure mimic of NEMO is necessary for potent inhibition. The rationally designed mimic engages vFLIP directly causing complex disruption, protein degradation and suppression of NF-κB signaling in primary effusion lymphoma (PEL). NEMO mimic treatment induces cell death and delays tumor growth in a PEL xenograft model. Our studies with this inhibitor reveal the critical nexus of signaling complex stability in the regulation of NF-κB by a viral oncoprotein.

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Kaposi's Sarcoma-Associated Herpesvirus vFLIP and Human T Cell Lymphotropic Virus Type 1 Tax Oncogenic Proteins Activate IκB Kinase Subunit γ by Different Mechanisms Independent of the Physiological Cytokine-Induced Pathways

Cited by 15 publications

References 21 publications

Tumour Immunogenicity, Antigen Presentation, and Immunological Barriers in Cancer Immunotherapy

Tumour Immunogenicity, Antigen Presentation, and Immunological Barriers in Cancer Immunotherapy

HTLV Tax: A Fascinating Multifunctional Co-Regulator of Viral and Cellular Pathways

Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics

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