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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）是一种感染和转化的三角洲型肿瘤逆转录病毒