Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

Tomita, Motowo; Semenza, G. L.; Michiels, C.; Matsuda, Tsuneo; Uchihara, Jun Nosuke; Okudaira, Taeko; Tanaka, Yosuke; Taira, Naoya; Ohshiro, Kazuiku; Mori, Nozomu

doi:10.1042/bj4340571

Cited by 6 publications

(6 citation statements)

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“…Hypoxia plays a fundamental role in the pathophysiology of common causes of mortality, including stroke . Zinc release from a subset of glutamatergic terminals heightens under ischemia , leading to extracellular zinc increase from nanomolar to micromolar levels . During synaptic transmission, zinc can be released into the surrounding milieu making it available for entry into cells through gated zinc channels on neighboring cells .…”

Section: Discussionmentioning

confidence: 99%

Zinc Promotes the Death of Hypoxic Astrocytes by Upregulating Hypoxia‐Induced Hypoxia‐Inducible Factor‐1alpha Expression via Poly(ADP‐ribose) Polymerase‐1

et al. 2013

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Aim Pathological release of excess zinc ions has been implicated in ischemic brain cell death. However, the underlying mechanisms remain to be elucidated. In stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) accumulation concurrently occur in the ischemic tissue. The present study testes the hypothesis that the presence of high intracellular zinc concentration is a major cause of modifications to PARP-1 and HIF-1α during hypoxia, which significantly contributes to cell death during ischemia. Methods Primary cortical astrocytes and C8-D1A cells were exposed to different concentrations of zinc chloride. Cell death rate and protein expression of HIF-1 and Poly(ADP-ribose) polymerase (PARP)-1 were examined after 3-hour hypoxic treatment. Results Although 3-hr hypoxia or 100 μM of zinc alone did not induce noticeable cytotoxicity, their combination led to a dramatic increase in astrocytic cell death in a zinc concentration dependent manner. Exposure of astrocytes to hypoxia for 3-hr remarkably increased the levels of intracellular zinc and HIF-1α protein, which was further augmented by added exogenous zinc. Notably HIF-1α knockdown blocked zinc-induced astrocyte death. Moreover, knockdown of PARP-1, another important protein in the response of hypoxia, attenuated the overexpression of HIF-1α and reduced the cell death rate. Conclusions Our studies show that zinc promotes hypoxic cell death through overexpression of the hypoxia response factor HIF-1α via the cell fate determine factor PARP-1 modification, which provides a novel mechanism for zinc-mediated ischemic brain injury.

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Section: Discussionmentioning

confidence: 99%

Zinc Promotes the Death of Hypoxic Astrocytes by Upregulating Hypoxia‐Induced Hypoxia‐Inducible Factor‐1alpha Expression via Poly(ADP‐ribose) Polymerase‐1

et al. 2013

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“…The viral oncoproteins vGPCR (expressed by KSHV) and HBx (expressed by HBV) up‐regulate HIF‐1α expression by activating the MAPK pathway. HCV and HTLV‐1 have also been shown to increase HIF‐1α transcription, although the viral proteins involved have not yet been elucidated . HBV HBx stabilizes HIF‐1α in normoxia by inhibiting its interaction with pVHL , whereas KSHV LANA stimulates degradation of pVHL, thereby increasing the cellular pool of HIF‐1α .…”

Section: Angiogenesismentioning

confidence: 99%

Viruses as key regulators of angiogenesis

Vrancken

Vervaeke

Balzarini

et al. 2011

Reviews in Medical Virology

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Angiogenesis is an important physiological process that is controlled by a precise balance of growth and inhibitory factors in healthy tissues. However, environmental and genetic factors may disturb this delicate balance, resulting in the development of angiogenic diseases, tumour growth and metastasis. During the past decades, extensive research has led to the identification and characterization of genes, proteins and signalling pathways that are involved in neovascularization. Moreover, increasing evidence indicates that viruses may also regulate angiogenesis either directly, by (i) producing viral chemokines, growth factors and/or receptors or (ii) activating blood vessels as a consequence of endothelial cell tropism, or indirectly, by (iii) modulating the activity of cellular proteins and/or (iv) inducing a local or systemic inflammatory response, thereby creating an angiogenic microenvironment. As such, viruses may modulate several signal transduction pathways involved in angiogenesis leading to changes in endothelial cell proliferation, migration, adhesion, vascular permeability and/or protease production. Here, we will review different mechanisms that may be applied by viruses to deregulate the angiogenic balance in healthy tissues and/or increase the angiogenic potential of tumours.

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“…Tax activation of Akt is also linked to NF-kappaB activation and p53 inhibition (76). Furthermore, activation of Akt by Tax prevents beta-catenin degradation and leads to its accumulation in the cell (81), and increases HIF-1alpha protein synthesis (82). Fukuda et al (75) reported high levels of phosphorylated Akt in ATLL cells and downregulated expression of inositol phosphatases PTEN and SH2-containing inositol phosphatase-1 (SHIP-1), which antagonize the PI3K-Akt pathway.…”

Section: Pi3k-aktmentioning

confidence: 99%

Cell signaling modifiers for molecular targeted therapy in ATLL

Mori¹

2009

Front Biosci

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Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of peripheral T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Available therapies for ATLL have minimal efficacy, with few responders and poor survival. New therapies are needed for ATLL patients. Three decades of research in this field has resulted in accumulation of a wealth of knowledge about the molecular pathways underlying the proliferation of HTLV-1-infected T cells. Inappropriate over- and under-activation of various signaling pathways can contribute to pathological processes such as neoplasia. Molecular and pharmacological interventions that target the aberrant state of activation are thus of potential therapeutic benefit. Here we review how signal transduction pathway components including nuclear factor-kappaB, activator protein-1, janus kinase-signal transducer and activator of transcription, and phosphatidylinositol 3-kinase-Akt contribute to the pathogenesis of ATLL. The targeted inhibition of such molecules to suppress the growth of HTLV-1-infected T cells both in vitro and in vivo is also discussed. The potential translation of such strategies into effective therapies for patients with ATLL may improve the poor outcome associated with this neoplasia.

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Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

Cited by 6 publications

References 0 publications

Zinc Promotes the Death of Hypoxic Astrocytes by Upregulating Hypoxia‐Induced Hypoxia‐Inducible Factor‐1alpha Expression via Poly(ADP‐ribose) Polymerase‐1

Zinc Promotes the Death of Hypoxic Astrocytes by Upregulating Hypoxia‐Induced Hypoxia‐Inducible Factor‐1alpha Expression via Poly(ADP‐ribose) Polymerase‐1

Viruses as key regulators of angiogenesis

Cell signaling modifiers for molecular targeted therapy in ATLL

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