Molecular mechanisms of telomerase activation by human papillomavirus E6

端粒酶的激活是超过85%的所有癌症的共同和特异性特征。除了端粒酶逆转录酶亚单位（TERT）外，“高危”人乳头瘤病毒的E6基因和c-myc癌基因也被认为能激活端粒酶。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，阐明了以下几点：1。HPV 16 E6和c-myc均通过诱导端粒酶的表达来激活端粒酶。E6和c-myc均不能激活原代人成纤维细胞的端粒酶活性.在原代人乳腺上皮细胞（HMEC）中，E6可激活端粒酶而不增加Myc，而E7可增加Myc水平但不能激活端粒酶。E6和E7联合表达对端粒酶的激活作用强于E6单独表达.利用酵母三杂交系统，我们分离到了能与E6/E6 AP复合物结合的新的细胞蛋白的cDNA，并制备了部分蛋白的抗血清。E6使转录因子Myc通过改变其染色质结构进入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增加Myc水平而强烈激活端粒酶. E6/E6 AP复合物可能增强推定的DNA结合蛋白的降解，所述DNA结合蛋白可以募集蛋白质，例如组蛋白脱乙酰酶。

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.