Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38
Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38
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DOI：
10.1096/fj.07-8389com
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发表时间：
2008-02-01
期刊：
影响因子：
4.8
通讯作者：
Tommasino, Massimo
中科院分区：
文献类型：
--
作者：
Gabet, Anne-Sophie;Accardi, Rosita;Tommasino, Massimo
属于HPV系统发育树β属的皮肤人乳头瘤病毒（HPV）类型似乎与非黑色素瘤皮肤癌相关。我们以前的研究表明，β HPV 38型E6和E7癌蛋白能够抑制肿瘤抑制因子p53和视网膜母细胞瘤。在这里，这两种病毒蛋白表达在原代人皮肤角质形成细胞，以研究其对端粒/端粒酶系统的影响。我们表明HPV 38 E6/E7诱导的皮肤角质形成细胞永生化与hTERT基因过表达相关。这一事件的部分原因是p53相关蛋白Delta Np 73的积累。尽管hTERTmRNA水平升高，但在HPV 38 E6/E7角质形成细胞中检测到的端粒酶活性低于在HPV 16 E6/E7角质形成细胞中观察到的端粒酶活性。高度增殖的HPV 38 E6/E7角质形成细胞中的低端粒酶活化导致存在极短且不稳定的端粒。此外，我们观察到后期桥，有丝分裂多极，和戏剧性的基因组畸变。有趣的是，hTERT的异位表达防止端粒侵蚀和基因组不稳定性。因此，我们发现，在HPV 38 E6/E7角质形成细胞的特征是不定期的增殖，端粒酶的次优活化和随后的广泛的端粒缩短导致基因组不稳定性，促进细胞永生化。
The skin human papillomavirus (HPV) types belonging to the genus beta of the HPV phylogenetic tree appear to be associated with nonmelanoma skin cancer. We previously showed that the beta HPV type 38 E6 and E7 oncoproteins are able to inactivate the tumor suppressors p53 and retinoblastoma. Here, both viral proteins were expressed in primary human skin keratinocytes in order to study their effects on the telomere/telomerase system. We show that immortalization of skin keratinocytes induced by HPV38 E6/E7 is associated with hTERT gene overexpression. This event is, in part, explained by the accumulation of the p53-related protein, Delta Np73. Despite elevated levels of hTERT mRNA, the telomerase activity detected in HPV38 E6/E7 keratinocytes was lower than that observed in HPV16 E6/E7 keratinocytes. The low telomerase activation in highly proliferative HPV38 E6/E7 keratinocytes resulted in the presence of extremely short and unstable telomeres. In addition, we observed anaphase bridges, mitotic multipolarity, and dramatic genomic aberrations. Interestingly, the ectopic expression of hTERT prevents both telomere erosion and genomic instability. Thus, we showed that in HPV38 E6/E7 keratinocytes characterized by unscheduled proliferation, suboptimal activation of telomerase and subsequent extensive telomere shortening result in genomic instability facilitating cellular immortalization.