Modulation of Host Cell Apoptotic Responses by HPVE7

描述（由申请人提供）：小DNA肿瘤病毒编码蛋白质，建立和/或维持复制能力细胞环境，允许在分化的、正常生长受阻的宿主细胞中进行复制。在没有同步环境刺激有丝分裂原的情况下，这种诱导异常细胞和/或病毒DNA合成会导致生长信号冲突的情况。这触发了细胞防御机制，即“热带哨兵反应”，通过细胞类型特异性流产过程（如细胞死亡、分化或衰老），将这些异常细胞从增殖池中清除。事实上，正常的二倍体成纤维细胞表达单个核癌基因，如腺病毒E1A、c-myc或人乳头瘤病毒(HPV)- 16e7，当其培养基被剥夺生长因子时，细胞会死亡。为了防止宿主细胞在复制过程中被消灭，人乳头状瘤病毒编码了一种互补功能E6，它可以中和热带哨点反应。这种病毒复制策略虽然非常有效，但对宿主细胞来说是一种冒险的提议。特别是在病毒基因表达失调的情况下，由于HPV基因组整合到宿主染色体中，感染细胞发生恶性转化的风险增加。HPV E7癌蛋白包含至少三个分子决定因素，保守区1同源结构域和pRB结合结构域以及羧基末端结构域，它们都有助于诱导异常DNA合成。我们的研究重点是通过这些E7序列确定相关的细胞蛋白复合物（目标1和2），并确定触发介导热带前哨反应的细胞信号通路（目标3）。这些研究可能揭示了治疗方式的机会，旨在揭示高危HPV相关病变和癌症中休眠的热带前哨信号。

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.