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Molecular mechanisms of telomerase activation by human papillomavirus E6

人乳头瘤病毒E6激活端粒酶的分子机制

基本信息

批准号：
11138267
负责人：
KIYONO Tohru
金额：
$ 4.8万
依托单位：
Aichi 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 (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11138267/
关键词：
human papillomavirus (HPV)E6 c-myc telomerase TERT ヒトパピローマウイルス(HPV)

项目摘要

Activation of telomerase is a common and specific feature in more than 85% of all cancers. In addition to the reverse transcriptase subunit of telomerase (TERT), the E6 gene of "high risk" human papillomavirus and the c-myc oncogene have been known to activate telomerase. In order to clarify the mechanisms activating telomerase, we examined the actions of these genes in activating telomerase, and elucidated the following points :l. Both HPV16 E6 and c-myc activate telomerase by inducing the expression of TERT.2. Neither E6 nor c-myc can activate telomerase in primary human fibroblasts.3. In primary human mammary epithelial cells (HMEC), E6 can activate telomerase without increasing Myc, while E7 can increase Myc level but cannot activate telomerase. Expression of E6 together with E7 can activate telomerase stronger than E6 alone can.4. With a yeast three hybrid system, cDNAs of novel cellular proteins that can bind to E6/E6AP complexes were isolated, and antisera against some of the proteins were raised.From these results, we led the following hypotheses :l. E6 enables the transcription factor Myc to access TERT locus by changing its chromatin structure.2. In HMEC expressing E6 and E7, E6 and E7 can strongly activate telomerase by opening the chromatin structure and increasing Myc level, respectively.3. E6/E6AP complexes might enhance degradation of a putative DNA binding protein(s) that can recruit proteins such as histone deacetylases.

端粒酶的激活是85%以上癌症的共同特征。除了端粒酶的逆转录酶亚基（TERT）外，已知“高风险”人乳头瘤病毒的E6基因和c-myc癌基因也能激活端粒酶。为了阐明端粒酶的激活机制，我们检测了这些基因在端粒酶激活中的作用，并阐明了以下几点：1。hpv16e6和c-myc均通过诱导TERT.2的表达激活端粒酶。E6和c-myc均不能激活人原代成纤维细胞的端粒酶。在原代人乳腺上皮细胞（HMEC）中，E6可以激活端粒酶，但不增加Myc，而E7可以增加Myc水平，但不能激活端粒酶。E6与E7联合表达对端粒酶的激活作用强于单独表达E6。利用酵母三杂交系统，分离了新的细胞蛋白与E6/E6AP复合物结合的cdna，并培养了部分蛋白的抗血清。根据这些结果，我们提出了以下假设：E6通过改变转录因子Myc的染色质结构使其能够进入TERT位点。在表达E6和E7的HMEC中，E6和E7分别通过打开染色质结构和提高Myc水平来强烈激活端粒酶。E6/E6AP复合物可能会促进一种假定的DNA结合蛋白的降解，这种结合蛋白可以招募蛋白质，如组蛋白去乙酰化酶。