Human Papillomavirus Manipulation of Epithelial Differentiation

人乳头瘤病毒对上皮分化的操纵

基本信息

批准号：
10164719
负责人：
Elizabeth A White
金额：
$ 40.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-14 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10164719
关键词：
3-Dimensional Address Anogenital cancer Antiviral Agents Apoptosis Automobile Driving Binding Biological Assay Biology Cancer Burden Cancer Etiology Cell Differentiation process Cell Line Cellular biology Collection Complement Cyclin-Dependent Kinase Inhibitor Data Environment Epithelial Epithelial Cells Gene Expression Genetic Transcription Genital Genitalia Goals HPV E7 HPV-High Risk Homeostasis Human Human Papillomavirus Human papilloma virus infection Impairment Knock-out Lesion Link Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Modeling Mutation Analysis Oncogenic Oncoproteins Protein Family Protein Tyrosine Phosphatase Proteins RB1 gene Reagent Regulation Research Personnel Retinoblastoma Role S Phase Signal Transduction Stratification Stratified Squamous Epithelium Testing Therapeutic Time Tropism Tumor Suppressor Proteins Update Variant Viral Genome Virus Virus Replication Work carcinogenicity defined contribution experimental study genetic regulatory protein high risk human model keratinocyte keratinocyte differentiation malignant oropharynx neoplasm multicatalytic endopeptidase complex notch protein novel therapeutic intervention premalignant protein complex retinoblastoma tumor suppressor tool two-dimensional virus host interaction

项目摘要

High-risk human papillomavirus (HPV) infection is responsible for nearly 5% of the global cancer burden. HPV infect stratified squamous epithelia and virus replication depends upon epithelial differentiation. To enable virus replication in differentiating cells, HPV-encoded proteins manipulate the cellular environment to promote proliferation and inhibit apoptosis. Much of this cellular reprogramming is enabled by the high-risk HPV E6 and E7 oncoproteins. High-risk HPV E7 bind and degrade the retinoblastoma tumor suppressor (RB1) to promote S- phase specific gene expression, thus driving proliferation and enabling viral genome replication. RB1 degradation is necessary, but not sufficient, for the oncogenic activity of high-risk HPV E7. Consequently, researchers have long sought to identify additional transforming activities of high-risk HPV E7. One candidate to account for this cooperative transforming activity is the protein tyrosine phosphatase PTPN14. PTPN14 is a putative tumor suppressor that is targeted for proteasome-mediated degradation by high-risk HPV E7 but not low-risk HPV E7. It inhibits the transcriptional co-regulator YAP1. We recently discovered that PTPN14 potently promotes epithelial differentiation. HPV E7 proteins inhibit differentiation and preliminary data suggests that this correlates with oncogenic activity and with PTPN14 degradation. This proposal tests the hypothesis that high-risk HPV E7 degrade PTPN14 to activate YAP1 and impair epithelial differentiation. The goal of the work is to integrate PTPN14 degradation into an updated model of oncogenic transformation by high-risk HPV. The aims are 1) to define the contribution of E7-mediated PTPN14 degradation to transformation and differentiation and 2) to determine the mechanism by which PTPN14 degradation represses differentiation. The current understanding of oncogenic transformation by HPV E6/E7 has not identified transforming activities that cooperate with RB1 inactivation nor does it explain how high-risk HPV oncoproteins impair differentiation. Our work will address both questions and we anticipate that it will define an additional activity required for HPV- mediated transformation. Because there are no antivirals available to treat existing HPV infections, identifying any new essential step in HPV-mediated transformation could have therapeutic potential. The ability to inhibit YAP1 and/or restore differentiation in HPV-positive cancers is especially promising. Understanding the mechanisms by which high-risk HPV inhibit differentiation will, in the long term, enable new therapeutic approaches in HPV-positive cancers and premalignant lesions.

高风险的人乳头瘤病毒（HPV）感染造成了近5％的全球癌症负担。 HPV感染分层的鳞状上皮和病毒复制取决于上皮分化。为了使病毒复制在分化细胞中，HPV编码的蛋白操纵细胞环境以促进增殖和抑制凋亡。高风险的HPV E6和E7癌蛋白实现了这种细胞重编程的大部分。高风险的HPV E7结合并降解视网膜细胞瘤抑制因子（RB1）以促进S相特异性基因表达，从而驱动增殖并实现病毒基因组复制。对于高风险HPV E7的致癌活性，RB1降解是必要但不足的。因此，研究人员长期以来一直试图确定高风险HPV E7的其他转型活动。考虑到这种合作转化活性的一个候选者是蛋白质酪氨酸磷酸酶PTPN14。 PTPN14是一种推定的肿瘤抑制剂，针对蛋白酶体介导的高风险HPV E7降解，而不是低风险HPV E7。它抑制转录共调控YAP1。我们最近发现PTPN14有效促进上皮分化。 HPV E7蛋白抑制分化和初步数据表明，这与致癌活性和PTPN14降解有关。该提案检验了高危HPV E7降解PTPN14以激活YAP1并损害上皮分化的假设。这项工作的目的是将PTPN14降解整合到高风险HPV的致癌转换模型中。目的是1）定义E7介导的PTPN14降解对转化和分化的贡献以及2）确定PTPN14降解抑制分化的机制。 HPV E6/E7对致癌转化的当前理解尚未确定与RB1失活合作的转化活动，也没有解释高风险的HPV HPV癌蛋白如何损害分化。我们的工作将解决这两个问题，我们预计它将定义HPV介导的转换所需的额外活动。由于没有可用于治疗现有HPV感染的抗病毒药，因此确定HPV介导的转化中的任何新基本步骤都可能具有治疗潜力。抑制HPV阳性癌症中YAP1和/或恢复分化的能力尤其有前途。从长远来看，了解高风险HPV抑制分化的机制将使HPV阳性癌症和预抗病变的新治疗方法能够实现新的治疗方法。