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Analyzing mechanism of oncogenesis by human papillomavirus

人乳头瘤病毒致瘤机制分析

基本信息

批准号：
14026065
负责人：
KIYONO Tohru
金额：
$ 18.24万
依托单位：
National Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14026065/
关键词：
Human Papillomavirus Cancer of uterine cervix immkortalization E6 E7 telomerase PDZ domain トランスフォーメーション PSD95 DLG4

项目摘要

Transforming activity of E6 requires the PDZ-binding motif at the carboxy terminus conserved among high risk HPV E6 proteins. Since we first reported the hDLG as the E6 target, hScrib, MUPP1, and MUGI have been reported as the similar targets. We identified PSD95 as a novel target. The fact that HPV positive cervical cancer cell lines showed very low expression levels of PSD95, allowed us speculate that PSD95 might function as tumor suppressor. Overexpression of PSD95 in CaSki cells unchanged the growth in a culture dish but significantly reduced the growth both in soft agar medium and nude mice. It was also suggested that PSD95 was ubiquitinated by E6/E6AP complex and degraded by proteosome.It has long been unknown how E6 activates telomerase in normal human keratinocyte and mammary epithelial cells. We found that E6/E6AP complex bound to a transcriptional repressor, NFX-1. From NIX-1 gene, 123 kDa (NFX1-123) and 91kDa (NFX1-91) proteins were expressed. We found E6/E6AP complex specifically enhanced degradation of NFX1-91 which functioned as transcriptional repressor of hTERT promoter, indicating that the enhanced degradation of NFX-1 is at least a mechanism to activate telomerase by E6.We suggest that the upregulation of hWAPL, which is preferentially overexpressed in cervical cancers, might be a mechanism which induces chromosomal instability in normal cells by E6 and E7. Human WAPL (hWAPL) is a human homologue of Drosophila wing apart-like gene. The gene product binds to heterochromatin and its overexpression can induce chromosomal instability in cultured cells.

E6的转化活性需要在高危HPV E6蛋白之间保守的羧基末端的PDZ结合基序。自从我们首次报道hDLG作为E6靶标以来，hScrib、MUPP1和Mugi被报道为类似的靶标。我们将PSD95确定为一个新的靶点。HPV阳性的宫颈癌细胞株PSD95的表达水平很低，这一事实使我们推测PSD95可能具有肿瘤抑制作用。在CaSki细胞中过表达PSD95不影响培养皿中的生长，但显着降低软琼脂和裸鼠的生长。也有人认为PSD95被E6/E6AP复合体泛素化，并被蛋白酶体降解。长期以来，E6如何激活正常人角质形成细胞和乳腺上皮细胞的端粒酶一直是未知的。我们发现E6/E6AP复合体与转录抑制因子NFX-1结合。Nix-1基因表达了123 kDa(NFX1-123)和91 kDa(NFX1-91)蛋白。我们发现E6/E6AP复合体特异性地促进了作为hTERT启动子转录抑制因子的NFX1-91的降解，表明NFX-1的增强降解至少是E6激活端粒酶的机制之一。我们认为，在宫颈癌中优先过表达的hWAPL的上调可能是E6和E7导致正常细胞染色体不稳定的机制之一。人WAPL(HWAPL)是果蝇类翼状基因的人类同源基因。该基因产物与异染色质结合，其过度表达可导致培养细胞的染色体不稳定。