Modulation of Host Cell Apoptotic Responses by HPVE7

描述(由申请人提供)：小型DNA肿瘤病毒编码的蛋白质建立和/或维持复制能力强的细胞环境，以允许在分化的、正常生长受阻的宿主细胞中复制。在没有同时环境有丝分裂原刺激的情况下，这种异常的细胞和/或病毒DNA合成的诱导导致了一种相互矛盾的生长信号的情况。这触发了一种细胞防御机制，即通过细胞类型特定的流产过程，如细胞死亡、分化或衰老，将这些异常细胞从增殖池中消除的“热带哨兵反应”。事实上，表达单个核癌基因的正常二倍体成纤维细胞，如腺病毒E1a、c-myc或人乳头瘤病毒(HPV)-16E7，当其培养基剥夺生长因子时会发生细胞死亡。为了防止在复制过程中消除宿主细胞，HPV编码了一个补充功能，E6，它中和了趋向性哨兵反应。虽然非常有效，但这样的病毒复制策略对宿主细胞来说是一个有风险的提议。尤其是在HPV基因组整合到宿主染色体导致的病毒基因表达失调的情况下，感染细胞发生恶性转化的风险增加。HPVE7癌蛋白包含至少三个分子决定簇，保守的第1区同源结构域、pRB结合域以及一个羧基末端结构域，每个结构域都能诱导DNA的异常合成。我们研究的重点是确定通过这些E7序列中的每一个(目标1和2)靶向的相关细胞蛋白复合体，并确定被触发以介导热带哨兵反应的细胞信号通路(目标3)。这些研究可能会揭示治疗方法的机会，这些治疗方法旨在揭示高危HPV相关病变和癌症中的休眠趋向性哨兵信号。

DESCRIPTION (provided by applicant): Small DNA tumor viruses encode proteins that establish and/or maintain a replication competent cellular milieu to permit replication in differentiated, normally growth arrested host cells. Such induction of aberrant cellular and/or viral DNA synthesis in the absence of concurrent environmental mitogen stimulation causes a situation of conflicting growth signals. This triggers a cellular defense mechanism, the "tropic sentinel response" that eliminates such deviant cells from the proliferative pool through cell-type specific abortive processes such as cell death, differentiation or senescence. Indeed, normal diploid fibroblasts that express single nuclear oncogenes such as adenovirus E1A, c-myc, or human papillomavirus (HPV)-16 E7 undergo cell death when their culture medium is deprived of growth factors. To prevent elimination of their host cells during replication, HPVs encode a complementing function, E6 that neutralizes the tropic sentinel response. While highly effective, such a viral replication strategy is a risky proposition for the host cell. Particularly under conditions of dysregulated viral gene expression that can result from integration of the HPV genome into a host chromosome an infected cell is at increased risk to undergo malignant transformation. The HPV E7 oncoprotein contains at least three molecular determinants, the conserved region 1 homology domain and the pRB binding domains as well as a carboxyl terminal domain that each contribute to the induction of aberrant DNA synthesis. The focus of our research is to identify relevant cellular protein complexes that are targeted through each of these E7 sequences (aims 1 & 2), and to determine the cellular signaling circuits that are triggered to mediate the tropic sentinel response (aim 3). These studies may reveal opportunities for therapeutic modalities designed to unmask the dormant tropic sentinel signal in high-risk HPV associated lesions and cancer.