Persistent activation of NF-κB by the Tax transforming protein of HTLV-1: hijacking cellular IκB kinases

Sun, Shao Cong; Ballard, Dean W.

doi:10.1038/sj.onc.1203220

Cited by 177 publications

(144 citation statements)

References 182 publications

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“…It is thought that the HTLV-encoded 40 kDa transactivator protein Tax mediates leukemic transformation in concert with Ras oncogene. 56 Tax induces NF-kB, 57 which can cause upregulation of the protein subunit of telomerase, human telomerase reverse transcriptase (hTERT), thus promoting long-term proliferation of genomically instable cells. 58 Tax expression can promote phosphorylation and activation of IKKa and IKKb by the kinase NF-kB-inducing kinase (NIK), and/or can directly bind to IKKg.…”

Section: B-cllmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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Section: B-cllmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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“…Finally, there are two chapters that describe the role of Rel/NF-kB signaling in viral leukemogenesis caused by human T-lymphotropic virus type 1 (HTLV-1) (Sun and Ballard, 1999) and Epstein-Barr virus (EBV) (Cahir McFarland et al, 1999).…”

Section: Organization Of This Collection Of Reviewsmentioning

confidence: 99%

The Rel/NF-κB signal transduction pathway: introduction

1999

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“…It is less clear how intracellular molecules, such as Tax, initiate signal transduction. Nevertheless, strong evidence suggests that Tax-mediated IKK activation does not involve cellular receptors or upstream signaling components (26). To understand the mechanism of IKK activation by Tax, we examined whether Tax alters the subcellular localization of individual IKK subunits in T lymphocytes.…”

Section: Tax Induces Relocalization Of Ikk Into Perinuclear Hotmentioning

confidence: 99%

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

Harhaj

Sun

Harhaj

2007

Journal of Biological Chemistry

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Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia. HTLV-1 encodes a trans-activating protein, Tax, which is largely responsible for the oncogenic properties of the virus. Tax promotes T cell transformation by deregulating the activity of various cellular factors, including the transcription factor NF-B. Tax activates the I B kinase (IKK) via physical interaction with the regulatory subunit, IKK␥, although it is unknown precisely how Tax activates the IKK complex. Here we show that Tax modulates the cellular localization of the IKK complex. The IKKs relocalize from a broad distribution in the cytoplasm to concentrated perinuclear "hot spots" in both HTLV-1-transformed lines and in Tax-expressing Jurkat cells. Relocalization of IKK is not observed with Tax mutants unable to activate NF-B, suggesting that only activated forms of IKK are relocalized. However, relocalization of IKK is strictly dependent on Tax expression because it does not occur in ATL cell lines that lack Tax expression or in Jurkat cells treated with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, IKK␥ is required for redistribution because cells lacking IKK␥ were unable to relocalize IKK␣ upon expression of Tax. We also find that Tax ubiquitination likely regulates IKK relocalization because mutation of three critical lysine residues in Tax renders it unable to relocalize IKK and activate the canonical and noncanonical NF-B pathways. Finally, we have observed that the perinuclear IKK in Tax-expressing cells colocalizes with the Golgi, and disruption of Golgi with either nocodazole or brefeldin A leads to a redistribution of IKK to the cytoplasm. Together, these results demonstrate that Tax induces relocalization of the IKK complex in a ubiquitin-dependent manner, and dynamic changes in the subcellular localization of the IKK complex may be critical for Tax function.The human T cell leukemia virus type I (HTLV-1) 3 is associated with adult T cell leukemia (ATL), an aggressive malignancy of CD4 ϩ T cells, and a neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (1). The HTLV-1 genome encodes a regulatory protein Tax in the pX region that plays a central role in HTLV-1-associated disease (2). Tax acts as a trans-activating protein that is critical for the expression of viral genes and also deregulates the expression of cellular genes. Tax regulates the expression of cellular genes by modulating signaling pathways such as NF-B, AP-1, CREB, and nuclear factor of activated T cells (3). Tax activation of NF-B is required for immortalization of T lymphocytes (4). Further, pharmacologic inhibition of NF-B leads to apoptosis of HTLV-1 transformed T cell lines and ATL cells (5).NF-B represents a family of transcription factors that regulate a wide variety of genes controlling cell survival, development, differentiation, and activation. NF-B family members include RelA (p65), c-Rel, RelB, p50, and p52, all of which contain a 300-amino acid Rel homology domain th...

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Persistent activation of NF-κB by the Tax transforming protein of HTLV-1: hijacking cellular IκB kinases

Cited by 177 publications

References 182 publications

Targeting NF-κB in hematologic malignancies

Targeting NF-κB in hematologic malignancies

The Rel/NF-κB signal transduction pathway: introduction

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

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