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 癌逆转录病毒，可感染并转化 CD4+ T 细胞并导致成人 T 细胞白血病/淋巴瘤 (ATLL)，这是一种侵袭性血液病通常对传统抗癌疗法具有抵抗力的恶性肿瘤 HTLV-1 的 3' 末端。基因组编码多种调节蛋白（即 Tax、Rex、HBZ、p8I、p12I、p13II 和 p30II）保守的核苷酸序列，称为 pX，在大多数 ATLL 临床分离株中保留。近四十年来，HTLV-1 作为通用信息模型得到了广泛研究病毒致癌作用；然而，迄今为止，其产品尚未被证明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具有功能相似性我的实验室已经鉴定出 HTLV-1 p30II 蛋白内的一个核心结构域与高危亚型人乳头瘤病毒 (hrHPV) 的 E6 癌蛋白同源均为 HTLV-1。 p30II 和 HPV E6 与细胞癌蛋白 c-Myc 协同作用，防止 p53 依赖性细胞凋亡通过抑制 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发生突变——尽管 E6 会降解 p53 蛋白，并通过与泛素连接酶 E6AP 相互作用显着降低其表达。我们的初步研究表明，HTLV-1 p30II 和 HPV16/18 E6 病毒癌蛋白诱导 TP53 诱导的糖酵解和细胞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)。 HPV+ 宫颈癌样本中 TIGAR 和 p53R2 水平升高，这与我们进一步表明，TIGAR 的慢病毒 siRNA 敲低可抑制致癌 c-Myc 表达。 HTLV-1 诱导 T 细胞异种移植模型中的体内肿瘤发生和转移性疾病进展根据这些发现，我们发现淋巴瘤和 HPV 诱导的鳞状细胞癌。不相关的 HTLV-1 和高危亚型 HPV 可能已经进化出类似的放松管制策略通过靶向 p53 功能来抑制宿主致癌和促生存信号通路。 R15 AREA 项目的目标是：1）阐明分子机制 HTLV-1 p30II 和高危 HPV E6 癌蛋白调节 p53 调节的促生存信号，2) 确定 TIGAR 和 p53R2 如何促进 HTLV-1 p30II 或 hrHPV E6 之间的合作癌蛋白和细胞癌基因，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成果。深入了解 HTLV-1 与其他致癌病毒之间的进化关系并取得进展我们对 p53 调节的促生存信号在病毒致癌作用中的作用的理解。