Linking IKKbeta activation to anti-autophagy in viral protein Tax-mediated oncoge

将 IKKbeta 激活与病毒蛋白 Tax 介导的肿瘤细胞中的抗自噬联系起来

基本信息

  • 批准号:
    8609543
  • 负责人:
  • 金额:
    $ 34.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-09-15 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): T cell leukemia virus type 1 (HTLV-1) is a causative factor for adult T cell leukemia and lymphoma (ATLL). HTLV-1 genome encodes a viral transforming protein, Tax1, which plays an essential role in initiating oncogenesis. One of the critical features that Tax1 contributes to oncogenesis is induction of persistent activation of NF-(B. Yet, how this activity correlates with T cell transformation remains unsolved. Our work demonstrates that Tax1 is a critical lipid raft modulator that can hijack I(B kinases (IKKs) to the lipid raft microdomains in HTLV-1-transformed T cells. It is well recognized that enrichment of IKKs in the lipid raft microdomains leads to activation of NF-(B in antigen-stimulated T cells. Tax1 is able to recruit IKKs persistently in lipid rafts, correlating with persistent NF-(B activity. We also find that Tax1 sequesters beclin 1 (BECN1) and Bif-1, the essential autophagy mediators, in lipid rafts in IKK(- dependent manner. Conversely, BECN1 represses Tax1 activation of NF-(B by inhibiting IKK(. Since loss of BECN1 or Bif-1 has been linked to spontaneous tumorigenesis including lymphoma, our findings strongly suggest that Tax1 links IKK( activation to oncogenesis partly through its anti-autophagy activity. The rationale for this proposal is based on the assumption that the axis of Tax1-IKK(-BECN1/Bif-1 leads to "loss of function" of the autophagy mediators. The proposed research is both innovative and significant, representing a new concept in filling a giant gap for our understanding about how Tax initiates oncogenic transformation of T cells. Our central hypothesis is that "HTLV-1 Tax suppresses autophagy by hijacking IKK( to lipid rafts leading to sequestration of the autophagy mediators in the microdomains, thereby contributing significantly to oncogenesis". We plan to investigate this hypothesis with following specific aims. Aim#1: Define the domain critical for lipid raft targeting of Tax1. We will determine the motifs and modifications such as ubiquitination crucial for lipid raft targeting of Tax1, identify a cellular factor in assisting lipid raft association of Tax1, and assess the importance of the lipid raft association of Tax1 in immortalizing primary human CD4+ T cells and in transforming NIH3T3 cells. Aim#2: Investigate the underlying mechanism of Tax1 to deregulate autophagy. We will investigate the mechanism of Tax1 in sequestrating Bif-1 and BECN1 in lipid rafts, evaluate the inhibitory effect of BECN1 on Tax1 activation of IKK(, and examine anti-autophagy and tumorigenic activity of Tax1 using MEF (Bif1+/+) and (Bif1-/-) cells. Aim#3: Determine oncogenic potential and anti-autophagy function of lipid raft-targeted IKK(. We will evaluate physical and functional interaction of IKK( with Bif-1 and BECN1 and assess anti-autophagy and in vitro transforming activities of the lipid raft-targeted IKK(. This study will help to decipher the pathological role of the axis of Tax- IKK(-BECN1/Bif-1 in HTLV-1 oncogenesis. PUBLIC HEALTH RELEVANCE: Adult T cell leukemia/lymphoma (ATLL) is caused by infection with human T cell leukemia virus type 1 (HTLV-1), infecting over 20 million patients worldwide. HTLV-1 encodes a viral oncogenic protein Tax, which plays an essential role in initiating malignancy of human T cells partly through persistent activation of NF-(B. We plan to investigate the mechanism that Tax mediates persistent activation of NF-(B and anti-autophagy function during development of T cell leukemia.
描述(申请人提供):T细胞白血病病毒1型(HTLV-1)是成人T细胞白血病和淋巴瘤(ATLL)的致病因素。HTLV-1基因组编码一种病毒转化蛋白Tax1,它在启动肿瘤发生中起着至关重要的作用。Tax1参与肿瘤发生的关键特征之一是诱导核因子-(B)的持续激活。然而,这种活性与T细胞转化的关系仍未解决。我们的工作表明Tax1是一个关键的脂筏调节剂,它可以劫持HTLV-1转化的T细胞中的I(B)激酶(IKKS)到脂筏微区。众所周知,IKKS在脂筏微区的富集会导致抗原刺激的T细胞中核因子-B的激活。Tax1能够在脂筏中持续招募IKK,这与持续的NF-(B)活性有关。我们还发现,在脂筏中,Tax1隔离物Beclin 1(BECN1)和Bif-1是重要的自噬介质,并以ikk(依赖)的方式存在。相反,BECN1通过抑制ikk(.由于BECN1或Bif-1的缺失与包括淋巴瘤在内的自发肿瘤发生有关,我们的发现强烈表明,Tax1(激活)与肿瘤发生有关,部分是通过其抗自噬活性。这一提议的理由是基于这样的假设,即Tax1-ikk(-BECN1/Bif-1)的轴导致自噬介体的“功能丧失”。这项研究具有创新性和重大意义,为我们理解税收如何启动T细胞致癌转化提供了一个新的概念,填补了一个巨大的空白。我们的中心假设是“HTLV-1 Tax通过劫持ikk(到脂筏,导致自噬介体隔离在微域中,从而显著促进肿瘤的发生)来抑制自噬”。我们计划以以下具体目标来研究这一假设。目的#1:确定Tax1脂筏靶向的关键结构域。我们将确定Tax1的脂筏靶向的关键基序和修饰(如泛素化),确定辅助Tax1脂筏结合的细胞因子,并评估Tax1的脂筏结合在原代人类CD4+T细胞永生化和转化NIH3T3细胞中的重要性。目的#2:研究Tax1去调控自噬的潜在机制。我们将研究Tax1在脂筏中隔离Bif-1和BECN1的机制,评价BECN1对IKK()的Tax1活性的抑制作用,并利用MEF(Bif1+/+)和(Bif1-/-)细胞检测Tax1的抗自噬和致瘤活性。目的#3:确定脂筏靶向的IKK(.我们将评估IKK(与Bif-1和BECN1的物理和功能相互作用,并评估脂筏靶向IKK()的抗自噬和体外转化活性。本研究将有助于破译TAX-IKK(-BECN1/Bif-1)轴在HTLV-1肿瘤发生中的病理作用。 公共卫生相关性:成人T细胞白血病/淋巴瘤(ATLL)是由人类T细胞白血病病毒1型(HTLV-1)感染引起的,全世界有超过2000万患者感染。HTLV-1编码一种病毒致癌蛋白TAX,它在启动人类T细胞恶性转化中起重要作用,部分是通过持续激活NF-B。我们计划研究TAX在T细胞白血病发生发展过程中介导NF-B持续激活和抗自噬功能的机制。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.
Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.
Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes.
鉴定 TBK1 和 IKKγ(非典型 IκB 激酶)作为 HTLV-1 转化的 T 淋巴细胞中关键的促生存因子。
  • DOI:
    10.1016/j.leukres.2016.04.012
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Zhang,Huan;Chen,Li;Cai,Shao-Hui;Cheng,Hua
  • 通讯作者:
    Cheng,Hua
Differential transforming activity of the retroviral Tax oncoproteins in human T lymphocytes.
  • DOI:
    10.3389/fmicb.2013.00287
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Ren T;Cheng H
  • 通讯作者:
    Cheng H
The autophagy molecule Beclin 1 maintains persistent activity of NF-κB and Stat3 in HTLV-1-transformed T lymphocytes.
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Hua Cheng其他文献

Hua Cheng的其他文献

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{{ truncateString('Hua Cheng', 18)}}的其他基金

Linking IKKbeta activation to anti-autophagy in viral protein Tax-mediated oncoge
将 IKKbeta 激活与病毒蛋白 Tax 介导的肿瘤细胞中的抗自噬联系起来
  • 批准号:
    7949419
  • 财政年份:
    2010
  • 资助金额:
    $ 34.97万
  • 项目类别:
Linking IKKbeta activation to anti-autophagy in viral protein Tax-mediated oncoge
将 IKKbeta 激活与病毒蛋白 Tax 介导的肿瘤细胞中的抗自噬联系起来
  • 批准号:
    8573179
  • 财政年份:
    2010
  • 资助金额:
    $ 34.97万
  • 项目类别:
Linking IKKbeta activation to anti-autophagy in viral protein Tax-mediated oncoge
将 IKKbeta 激活与病毒蛋白 Tax 介导的肿瘤细胞中的抗自噬联系起来
  • 批准号:
    8139137
  • 财政年份:
    2010
  • 资助金额:
    $ 34.97万
  • 项目类别:

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