Cellular Targets of Papillomavirus Oncoproteins

人类乳头瘤病毒(HPV)与特定的人类癌症有关，最明显的是人类宫颈癌。现在已经描述了100多种不同的HPV，其中大约25种与肛门生殖道病变有关。根据与其相关的临床损害，这些肛门生殖器相关的HPV可以进一步细分为两组。“低风险”的HPV(例如HPV-6和HPV-11)与良性生殖器疣或尖锐湿疣有关，而良性生殖器疣或尖锐湿疣仅极少进展为癌症，而“高风险”的HPV(例如HPV16和HPV18)与可进展为癌症的上皮内肿瘤有关。大约95%的人类宫颈癌 含有和病毒DNA来自“高危”的HPV型，并表达HPVE6和E7基因。这与独立的分子证据一起有力地表明，由“高危”HPV的E6和E7基因编码的蛋白质直接促进了HPV阳性癌症的致癌进展。E7蛋白在细胞转化中发挥作用，至少部分是通过与视网膜母细胞瘤易感基因pRb的产物以及其他pRb相关的“口袋蛋白”的相互作用。由生殖道、癌症相关的人乳头瘤病毒编码的E6癌蛋白的主要靶点是P53肿瘤抑制蛋白。然而，一些证据表明，这些HPVE6和E7癌蛋白有额外的细胞靶点。此外，致癌的牛乳头状瘤病毒(BPV)E6和 E7癌蛋白不会通过依赖于p53和pRb的途径引起转化。该项目的具体目标是检查乳头瘤病毒E6和E7蛋白的其他靶点，这些靶点可能对它们的转化功能很重要。有两个主要的特定目的，一个涉及E6蛋白，第二个涉及E7蛋白。我们将扩大我们对HPV16E6蛋白的研究，目标是C末端Src激酶(CSK)的泛素化和蛋白分解以及随后的Src家族激酶Fyn的激活。我们还启动了使用BPVE7的串联亲和纯化的蛋白质组筛选。我们将探索E7与微管相关因子(MTAF600)相互作用的潜在意义。

The human papillomaviruses (HPVs) are associated with specific human cancers, most notably human cervical cancer. More than 100 different HPVs have now been described and approximately 25 of these are associated with lesions of the anogenital tract. These anogenital associated HPVs can be further subdivided into two groups on the basis of the clinical lesions with which they are associated. The "low risk" HPVs (e.g. HPV-6 and HPV- 11) are associated with benign genital warts or condyloma acuminata that only very rarely progress to cancers, whereas the "high risk" HPVs (e.g. HPV16 and HPV18) are associated with intraepithelial neoplasias that can progress to cancer. Approximately 95% of human cervical cancers contain and viral DNA from a "high risk" HPV type and express the HPV E6 and E7 genes. This, along with independent molecular evidence, suggests strongly that the proteins encoded by the E6 and E7 genes of the "high risk" HPVs contribute directly to carcinogenic progression in the HPV positive cancers. The E7 proteins functions in cellular transformation, at least in part, through interactions with the product of the retinoblastoma susceptibility gene, pRB, and the other pRB related "pocket proteins". The major target of the E6 oncoprotein encoded by the genital tract, cancer associated human papillomaviruses is the p53 tumor suppressor protein. However, several lines of evidence indicate that these HPV E6 and E7 oncoproteins have additional cellular targets. Furthermore, the oncogenic bovine papillomavirus (BPV) E6 and E7 oncoproteins do not cause transformation by p53 and pRB dependent pathways. The specific aims of this project are designed to examine additional targets of the papillomavirus E6 and E7 proteins that may be important to their transformation functions. There are two major specific aims, one involving the E6 protein and the second the E7 protein. We will extend our studies on the HPV16 E6 protein targeting the ubiquitination and proteolysis of the C-terminal Src kinase (Csk) and the consequent activation of the Src family kinase Fyn. We have also initiated a proteomic screen using tandem affinity purification using BPV E7. We will explore the potential significance of the interaction of E7 with the microtubule-associated factor (MTAF600).