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
- 来源:
- 关键词:AcetylationAcetyltransferaseAdult T-Cell Leukemia/LymphomaAffinity ChromatographyAlgorithmsAmino AcidsApoptosisApoptosis Regulation GeneApoptoticBase SequenceCD4 Positive T LymphocytesCRISPR/Cas technologyCancer EtiologyCancer PatientCell LineCellsCervix carcinomaClinicalDisease ProgressionEngraftmentFamilyGenesGenetic TranscriptionGenomeGlycolysis InductionGrowthHPV-High RiskHTATIP geneHematologic NeoplasmsHumanHuman PapillomavirusHuman T-lymphotropic virus 1Human papillomavirus 16HypoxiaIndividualInfiltrationInhibition of ApoptosisKineticsLaboratoriesLinkLysineMaintenanceMalignant NeoplasmsMalignant neoplasm of cervix uteriMapsMediatingMessenger RNAMitochondriaModelingMolecularMutateOncogenicOncogenic VirusesOncologyOncoproteinsOpen Reading FramesOrganPapillomavirus Transforming Protein E6Pathway interactionsPatient IsolationPatientsPeripheral Blood Mononuclear CellPhosphopeptidesPhosphotransferasesPlayPrimatesProteinsProto-OncogenesRegulator GenesResearch TrainingResistanceRibonucleotide ReductaseRoleSamplingScienceSerine Phosphorylation SiteSignal PathwaySignal TransductionSmall Interfering RNASpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSquamous cell carcinomaT-Cell LymphomaT-LymphocyteTP53 geneTaxesTrans-ActivatorsTransformed Cell LineTumor TissueUBE3A geneViralVirusVirus DiseasesXenograft Modelanti-cancer therapeuticc-myc Genescancer therapycarcinogenesiscell growthcell immortalizationcofactorexperimental studygenetic regulatory proteingraduate studenthigh riskhuman modelin vivoinsightknock-downleukemianeoplasticpreventtherapeutic targettraining opportunitytranscriptometranscriptome sequencingtransforming virustumortumorigenesisubiquitin ligaseundergraduate studentviral carcinogenesisvirus related cancer
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δ肿瘤逆转录病毒,
CD 4 + T细胞,并导致成人T细胞白血病/淋巴瘤(ATLL),一种侵袭性血液系统疾病,
通常对常规抗癌疗法具有抗性的恶性肿瘤。HTLV-1的3'端
基因组编码几种调节蛋白(即,税、雷克斯、HBZ、p8 I、p12 I、p13 II和p30 II)来自高度-
保守的核苷酸序列,称为pX,其保留在大多数ATLL临床分离株中。
近四十年来,HTLV-1作为一种通用的信息模型被广泛研究,
病毒致癌作用;然而,迄今为止,其产物均未显示含有结构或
与灵长类T细胞嗜淋巴细胞病毒(PTLV)以外的其他致癌病毒功能相似
家人我的实验室已经确定了HTLV-1 p30 II蛋白的核心结构域,
与高危亚型人乳头瘤病毒(hrHPV)的E6癌蛋白同源。HTLV-1
p30 II和HPV E6与细胞癌蛋白c-Myc协同作用,阻止p53依赖性凋亡
通过抑制TIP 60介导的p53蛋白在赖氨酸残基K120上的乙酰化。有趣的是,p53是
在HTLV-1+ ATLL和HPV+宫颈癌临床分离株中很少突变-尽管E6降解了
p53蛋白,并通过与泛素连接酶E6 AP的相互作用显著降低其表达。
我们的初步研究表明HTLV-1 p30 II和HPV 16/18 E6病毒癌蛋白
诱导TP 53诱导的糖酵解和凋亡的表达和线粒体定位
调节子(TIGAR)和p53诱导型核糖核苷酸还原酶(p53 R2)。原发性患者源性ATLL
HPV+宫颈癌样品含有升高水平的TIGAR和p53 R2,其与
致癌c-Myc表达。我们进一步表明,TIGAR的慢病毒siRNA敲低抑制了
HTLV-1诱导T细胞异种移植模型中体内肿瘤发生和转移性疾病进展
淋巴瘤和HPV诱导的鳞状细胞癌。基于这些发现,我们假设,
不相关的HTLV-1和高危亚型HPV可能已经进化出类似的策略,
宿主致癌和促生存信号通路的靶向p53功能。以下具体
R15 AREA项目的主要目标是:1)阐明
HTLV-1 p30 II和高危HPV E6癌蛋白调节p53调节的促存活信号,2)
确定TIGAR和p53 R2如何促进HTLV-1 p30 II或hrHPV E6之间的合作
癌蛋白和细胞癌基因,和3)阐明这些p53调节的促生存的作用,
HTLV-1和HPV诱导的体内肿瘤发生中的信号。拟议的研究将产生有价值的新的
HTLV-1与其他致癌病毒的进化关系及其研究进展
我们对p53调节的促生存信号在病毒致癌作用中的作用的理解。
项目成果
期刊论文数量(0)
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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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