Activation of NF-kB by Human Papillomaviruses

人乳头瘤病毒对 NF-kB 的激活

• 批准号: 7032222
• 负责人: CRAIG Duncan WOODWORTH
• 金额: $ 0.25万
• 依托单位: CLARKSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032222
• 关键词: Activation; NF; kB; Human; Papillomaviruses

DESCRIPTION (provided by applicant): Infection with a subset of human papillomaviruses (HPV) is the major risk factor for cervical cancer. The HPV E6 and E7 viral genes are selectively retained and expressed in most cervical cancer cells where they activate DNA synthesis and interfere with multiple regulatory pathways. We have found that expression of HPV-16 E6 and E7 genes in epithelial cells cultured from human cervix activates the transcription factor NF-kB and stimulates expression of multiple genes known to be NF-kB-responsive. This is important because NF-kB is a key mediator of the inflammatory and innate immune responses. NF-kB stimulates the host response to stress by activating genes that promote cell growth and survival, and constitutive activation of NF-kB contributes to malignant development. We hypothesize that activation of NF-kB provides cervical epithelial cells with a selective survival advantage and represents an important step in immortalization by HPV. The proposed work will address 2 related questions: 1) How do the E6 and E7 viral proteins activate NF-kB in different cell types of the reproductive tract? 2) Does NF-kB activation in HPV-infected cervical cells enhance cell growth, survival, or immortalization? Our results will clarify whether NF-kB is a potential target for therapy of HPV infection or cervical dysplasia. Epithelial cells contribute to innate immunity in the reproductive tract, and NF-kB is a central regulator of the inflammatory and innate immune responses. Therefore, our results will provide basic information on how HPV might alter host response to infection.

描述（由申请人提供）： 人乳头瘤病毒 (HPV) 子集的感染是宫颈癌的主要危险因素。 HPV E6 和 E7 病毒基因在大多数宫颈癌细胞中选择性保留和表达，它们激活 DNA 合成并干扰多种调控途径。我们发现，人宫颈培养的上皮细胞中 HPV-16 E6 和 E7 基因的表达会激活转录因子 NF-kB，并刺激已知具有 NF-kB 反应性的多个基因的表达。这很重要，因为 NF-kB 是炎症和先天免疫反应的关键介质。 NF-kB 通过激活促进细胞生长和存活的基因来刺激宿主对应激的反应，并且 NF-kB 的组成型激活有助于恶性发展。我们假设 NF-kB 的激活为宫颈上皮细胞提供了选择性生存优势，并且代表了 HPV 永生化的重要一步。拟议的工作将解决 2 个相关问题：1）E6 和 E7 病毒蛋白如何激活生殖道不同细胞类型中的 NF-kB？ 2) HPV 感染的宫颈细胞中的 NF-kB 激活是否会增强细胞生长、存活或永生化？我们的结果将阐明 NF-kB 是否是治疗 HPV 感染或宫颈发育不良的潜在靶点。上皮细胞有助于生殖道的先天免疫，而 NF-kB 是炎症和先天免疫反应的中心调节因子。因此，我们的结果将提供有关 HPV 如何改变宿主对感染的反应的基本信息。