Mechanisms of human papillomavirus E6/E7 expression during cellular differentialtion of cervical cancer

人乳头瘤病毒E6/E7表达在宫颈癌细胞分化过程中的机制

• 批准号: 08671876
• 负责人: KYO Satoru
• 金额: $ 1.6万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671876/
• 关键词: HPV; Cervical cancer; Cell differentiation; Transcription factor; 転写調節; AP1; YY1; ヒトパピローマウイルス; 癌遺伝子

To clarify the molecular mechanisms through which human papillomavirus E6/E7 expression is activated during the process of cellular differentiation in stratified epithelial cells of uterine cervix, we identified core enhancer of upstream regulatory region of HPV3 1 b E6/E7 genes using transient expression assays. DNA foot print analyses and gel shift analyses identified sevral nuclear factors which bind core enhancer and regulate transcription of E6/E7 genes. In particular, Ap1 was found to be the most potent transactivator. In situ hybridization analyses revealed that E6/E7 mRNA was expressed mainly in the undifferentiated basal layers of stratified epithelial cells in uterine cervix, which was co-localized with AP1 expression determined by immunohistochemical analyses. These findings suggest that AP1 is the critical determinant of HPV oncogene expression. In addition, we found that cellular factor YY1 cooperates with API to achieve full activation of HPV oncogene expression. These results may provide insight into molecular targets for gene therapies against cervical cancer induced by HPV infection.

为阐明人乳头瘤病毒E6/E7基因在子宫颈上皮细胞分化过程中表达激活的分子机制，我们采用瞬时表达分析法鉴定了HPV 3 1 B E6/E7基因上游调控区的核心增强子。DNA足迹分析和凝胶位移分析鉴定了与核心增强子结合并调控E6/E7基因转录的几种核因子。特别是，发现Ap 1是最有效的反式激活因子。原位杂交结果显示，E6/E7 mRNA主要表达于子宫颈复层上皮细胞未分化的基底层，与免疫组化结果显示的AP 1表达共定位。这些结果表明，AP 1是HPV癌基因表达的关键决定因素。此外，我们发现细胞因子YY 1与API协同作用，实现HPV癌基因表达的完全激活。这些结果可能为HPV感染诱导的宫颈癌基因治疗提供分子靶点。

项目成果

Satoru Kyo,David Masaki Inoue.et al: "Expression of AP1 during cellnlan differentiation determines human papillomarims E6/E7 expression in stratified epithelal all" Journal of General Virology. 78. 401-411 (1997)

Satoru Kyo、David Masaki Inoue.et al：“cellnlan 分化过程中 AP1 的表达决定了分层上皮细胞中人乳头状瘤 E6/E7 的表达”《普通病毒学杂志》。

"The 5'Region of the Human Papillomavirus Type 31 Upstream Regulatory Region Acts as an Enhancer which Augments Viral Early Expression Thrugh the Action of YY1" Virology. 237. 159-169 (1997)

“人乳头瘤病毒 31 型上游调节区的 5 区域充当增强子，通过 YY1 的作用增强病毒早期表达”病毒学。

Tan Kanaya, Satoru Kyo Laimins A reimonis: "The 5' region of the human porpilloma Virus type 31 upstream rignlatory region acts as an enbehave which Angments viral early expression" Virology. 237. 159-169 (1997)

Tan Kanaya、Satoru Kyo Laimins A reimonis：“人孔雀瘤病毒 31 型上游的 5 区域充当了影响病毒早期表达的行为”病毒学。

Kyo.S et al: "Transcrptional activity of HPV31b enhancer is regultaed through synergistic interaction of AP1 with two novel factor" Virology. 211. 184-197 (1995)

Kyo.S 等人：“HPV31b 增强子的转录活性是通过 AP1 与两个新因子的协同相互作用来调节的”病毒学。