Activation of NF-kB by Human Papillomaviruses

描述（由申请人提供）：感染人乳头瘤病毒（HPV）的一个子集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，激活DNA合成并干扰多种调控途径。我们发现人宫颈上皮细胞中HPV-16 E6和E7基因的表达可激活转录因子NF-kB，并刺激多种已知的NF-kB应答基因的表达。这一点很重要，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，NF-kB的组成性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，并代表了HPV永生化的重要一步。提出的工作将解决两个相关问题：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NF-kB激活是否能促进细胞生长、存活或永生？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。上皮细胞参与生殖道先天免疫，NF-kB是炎症和先天免疫反应的中枢调节因子。因此，我们的结果将为HPV如何改变宿主对感染的反应提供基本信息。

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.