前人的研究發現高危險性類型人類乳突瘤病毒 (HPV) 主要含有兩個誘發細胞癌化的致癌蛋白質，分別為 E6 和 E7 蛋白質，當各自將 E6 與 E7 表現於初代細胞 (primary cell) 時，會導致細胞發生轉型。在細胞癌化的過程中，E6 及 E7 會分別影響宿主細胞中的 p53 及 pRB 蛋白質表現，藉此干擾宿主細胞內之生長週期與恆定，此現象已被廣泛探討。然前人的研究指出 E7 發生突變時，若 E7 僅與 pRB 結合，並不足以造成細胞發生轉型，此結果說明除與 pRB 的結合之外，與宿主其它蛋白質之交互作用亦是 E7 導致細胞轉型的成因。
本研究室前人研究中，已發現並陸續呈述 HPV-16E7 或 -18E7 會調控細胞的其它蛋白質，例如：c-myc 、USP11、DYRK1A 和 TIEG1 (Klf10) 等，而在酵母菌雙雜合系統篩選結果中，初步發現 DDB1 與 HPV-16E7 之間會形成複合體。目前研究指出 DDB1 為 DDB (DNA damage-binding protein) 異型二聚複合體的一個亞單位，其在核苷酸切除修復機制中扮演重要的角色。本論文結果發現 HPV-16E7 的確會與 DDB1 結合，並在胞外實驗中 （in vitro） 藉由進行序列刪除型的 HPV-16E7 蛋白質 GST pull down，發現 HPV-16E7 是以 CRI 及 CRIII 鋅指結構域與 DDB1 結合。再者，於胞內實驗中 （in vivo） 以共免疫沈澱法亦證實 HPV-16E7 的確會與 DDB1 具交互作用；為確認 HPV-16E7 存在是否對 DDB1 的表現量與穩定度具影響性，分別以 H1299 細胞株及 MCF7 細胞株進行研究，結果發現當將 HPV-16E7 分別轉染兩細胞株時，皆會導致內生性 DDB1 蛋白質量減少，另添加轉譯抑制藥物環己醯亞胺 (Cycloheximide) 觀測其蛋白質的半衰期，亦證實有此現象發生。
由於 DDB1 參與 DNA 修復及其為 E3 泛素黏酶辨識受質，因此參與許多維持細胞恆定所須蛋白質的降解反應，綜合由過去文獻顯示，許多病毒的致癌蛋白會與宿主的 DDB1 E3泛素黏酶進行結合，藉以調控宿主其它蛋白質的表現，本研究新發現 DDB1 為一可被 HPV-16E7 所調控的胞內蛋白質，而其可能藉由調控此蛋白質造成被感染細胞發生轉型作用。

The functions of two viral onco-proteins, E6 and E7, from high-risk human papillomavirus (HPV), are reflected in many of the cancer signaling. The expression of E6 or E7 alone in primary cells has been known resulting the cells transform. The effects of E6 on p53 and E7 on pRb during carcinogenesis have been extensively investigated which regulate cells growth and homeostasis. However, a detailed mutagenesis study on E7 also revealed that binding to pRb alone is insufficient to cause cells transformation. This result suggests in addition to binding to pRb, other protein-protein interactions are necessary for the E7-mediated transformation.
In our earlier studies, we have been characterized and showed some cellular proteins that it is modulated in HPV-16E7 or -18E7 presented such as c-myc, USP11, DYRK1A and TIEG1 (Klf10) etc.. One of other candidates from the yeast two-hybrid assay, we first found that the DDB1 interacts and forms a specific complex with HPV-16E7. DDB1 is one subunit of DNA damage-binding heterodimer protein complex which play an important functions in nucleotide excision repair. In this thesis, we have demonstrated that E7 does indeed interact with DDB1 and a sequential deletion analysis of E7 maps the DDB1 interaction site to the CRI and CRIII zinc finger domains by GST pull down in vitro. Moreover, a co-immunoprecipitation assay was also adopted to confirm this interaction in vivo. Furthermore, in order to analyze whether the presence of HPV-16E7 affects expression and stability of DDB1 protein in H1299 and MCF7 cells respectively. This result indicated that transfected HPV-16E7 in both cells cause the protein reduction of endogenous DDB1. In the meantime, a protein-half life assay verified this regulation when added translation inhibitor-cycloheximide in culture medium.
Due to the DDB1 protein involved in DNA repair as well as a subunit of E3 ubiquitin ligase recognized substrate, and further involved in many cellular proteins degradation. Taken together, this study found that HPV-16E7 associated with another intracellular protein and probably through the regulation of this protein to cause the transformation of infected cells.

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