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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：
ROBERT L HARROD
金额：
$ 44.55万
依托单位：
SOUTHERN METHODIST UNIVERSITY
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：
https://reporter.nih.gov/project-details/10572142
关键词：
Acetylation Acetyltransferase Adult T-Cell Leukemia/Lymphoma Affinity Chromatography Algorithms Amino Acids Apoptosis Apoptosis Regulation Gene Apoptotic Base Sequence CD4 Positive T Lymphocytes CRISPR/Cas technology Cancer Etiology Cancer Patient Cell Line Cells Cervix carcinoma Clinical Disease Progression Engraftment Family Genes Genetic Transcription Genome Glycolysis Induction Growth HPV-High Risk HTATIP gene Hematologic Neoplasms Human Human Papillomavirus Human T-lymphotropic virus 1 Human papillomavirus 16 Hypoxia Individual Infiltration Inhibition of Apoptosis Kinetics Laboratories Link Lysine Maintenance Malignant Neoplasms Malignant neoplasm of cervix uteri Maps Mediating Messenger RNA Mitochondria Modeling Molecular Mutate Oncogenic Oncogenic Viruses Oncology Oncoproteins Open Reading Frames Organ Papillomavirus Transforming Protein E6 Pathway interactions Patient Isolation Patients Peripheral Blood Mononuclear Cell Phosphopeptides Phosphotransferases Play Primates Proteins Proto-Oncogenes Regulator Genes Research Training Resistance Ribonucleotide Reductase Role Sampling Science Serine Phosphorylation Site Signal Pathway Signal Transduction Small Interfering RNA Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Squamous cell carcinoma T-Cell Lymphoma T-Lymphocyte TP53 gene Taxes Trans-Activators Transformed Cell Line Tumor Tissue UBE3A gene Viral Virus Virus Diseases Xenograft Model anti-cancer therapeutic c-myc Genes cancer therapy carcinogenesis cell growth cell immortalization cofactor experimental study genetic regulatory protein graduate student high risk human model in vivo insight knock-down leukemia neoplastic prevent therapeutic target training opportunity transcriptome transcriptome sequencing transforming virus tumor tumorigenesis ubiquitin ligase undergraduate student viral carcinogenesis virus 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， CD4 + 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，Tax、雷克斯、HBZ、p8 I、p12 I、p13 II和p30 II），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TIP60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E6AP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TP53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（p53R2）。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-敲除抑制了 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。