Roles of p53-Regulated Pro-Survival Signals in Carcinogenesis by HTLV-1 and High-Risk Subtype HPVs

p53 调节的促生存信号在 HTLV-1 和高危亚型 HPV 致癌过程中的作用

基本信息

  • 批准号:
    10572142
  • 负责人:
  • 金额:
    $ 44.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-13 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

The human T-cell leukemia virus type-1 (HTLV-1) is a delta oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive hematological malignancy that is generally resistant to conventional anticancer therapies. The 3' end of the HTLV-1 genome encodes several regulatory proteins (i.e., Tax, Rex, HBZ, p8I, p12I, p13II, and p30II) from a highly- conserved nucleotide sequence, known as pX, which is retained in the majority of ATLL clinical isolates. For nearly four decades, the HTLV-1 has been extensively studied as a general informative model for viral carcinogenesis; however, to date, none of its products have been shown to contain structural or functional similarities to other oncogenic viruses beyond the primate T-cell lymphotropic virus (PTLV) family. My laboratory has identified a core structural domain within the HTLV-1 p30II protein with homology to the E6 oncoproteins of high-risk subtype human papillomaviruses (hrHPVs). Both HTLV-1 p30II and HPV E6 cooperate with the cellular oncoprotein, c-Myc, and prevent p53-dependent apoptosis by inhibiting TIP60-mediated acetylation of the p53 protein on lysine residue K120. Intriguingly, p53 is rarely mutated in HTLV-1+ ATLL and HPV+ cervical cancer clinical isolates –although E6 degrades the p53 protein and significantly reduces its expression through interactions with the ubiquitin ligase, E6AP. Our preliminary studies have demonstrated that the HTLV-1 p30II and HPV16/18 E6 viral oncoproteins induce the expression and mitochondrial localization of the TP53-induced glycolysis and apoptosis regulator (TIGAR) and p53-inducible ribonucleotide reductase (p53R2). Primary patient-derived ATLL and HPV+ cervical carcinoma samples contain elevated levels of TIGAR and p53R2 that correlate with oncogenic c-Myc expression. We have further shown that lentiviral-siRNA-knockdown of TIGAR inhibits in vivo tumorigenesis and metastatic disease progression in xenograft models of HTLV-1-induced T-cell lymphoma and HPV-induced squamous cell carcinoma. Based upon these findings, we hypothesize that the unrelated HTLV-1 and high-risk subtype HPVs may have evolved similar strategies to deregulate host oncogenic and pro-survival signaling pathways by targeting p53 functions. The following Specific Aims are proposed for this R15 AREA project: 1) to elucidate the molecular mechanisms by which the HTLV-1 p30II and high-risk HPV E6 oncoproteins modulate p53-regulated pro-survival signals, 2) to determine how TIGAR and p53R2 contribute to the cooperation between HTLV-1 p30II or hrHPV E6 oncoproteins and cellular oncogenes, and 3) to elucidate the roles of these p53-regulated pro-survival signals in HTLV-1 and HPV-induced tumorigenesis in vivo. The proposed studies will yield valuable new insight into the evolutionary relationship between HTLV-1 and other cancer-inducing viruses and advance our understanding of the roles of p53-regulated pro-survival signals in viral carcinogenesis.
人类t细胞白血病病毒1型(HTLV-1)是一种感染和转化的三角洲型肿瘤逆转录病毒

项目成果

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ROBERT L HARROD其他文献

ROBERT L HARROD的其他文献

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{{ truncateString('ROBERT L HARROD', 18)}}的其他基金

Coordinate Regulation of p53 and c-MYC in an HTLV-1 Model of Carcinogenesis
HTLV-1 致癌模型中 p53 和 c-MYC 的协调调节
  • 批准号:
    8232612
  • 财政年份:
    2012
  • 资助金额:
    $ 44.55万
  • 项目类别:

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