The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability.
The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability.
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发表时间：
2002-12
期刊：
影响因子：
11.2
通讯作者：
S. Duensing;K. Münger
中科院分区：
文献类型：
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作者：
S. Duensing;K. Münger
基因组不稳定性的发展是高危型人乳头瘤病毒（HPV）相关宫颈癌发生的标志。我们先前已经证明HPV-16 E7癌蛋白通过诱导异常的中心体数目和多极有丝分裂纺锤体而迅速破坏有丝分裂的保真度。在这里，我们报告HPV-16 E6和E7的表达独立地导致各种有丝分裂异常。HPV-16 E6和E7分别与未对齐或落后的染色体物质相关，表明纺锤体检查点控制放松。此外，通过压倒性的检查点控制机制，可能会阻止具有多个纺锤体极性的细胞进入后期，HPV-16 E6和E7的表达导致少量但显著数量的细胞在细胞分裂过程的后期阶段具有改变的极性。除了有可能引起染色体数量失衡的变化外，我们发现HPV-16 E7的表达可以触发后期桥形成，其程度与高危HPV E6相似。后期桥通常发生在染色体断裂和染色体结构改变之后。进一步研究HPV-16 E6和E7导致宿主细胞基因组不稳定的机制，发现两种高危HPV癌蛋白均诱导DNA损伤。此外，HPV-16 E7的表达与表现出磷酸化组蛋白H2 AX的核灶的细胞数量增加以及由DNA修复触发的细胞周期检查点的激活相关。因此，我们的研究结果表明，HPV癌蛋白是一个来源的数量和结构染色体不稳定性在HPV相关的致癌作用。
The development of genomic instability is a hallmark of high-risk human papillomavirus (HPV) associated cervical carcinogenesis. We have previously shown that the HPV-16 E7 oncoprotein rapidly subverts mitotic fidelity by inducing abnormal centrosome numbers and multipolar mitotic spindles. Here we report that expression of HPV-16 E6 and E7 independently results in various mitotic abnormalities. HPV-16 E6 and E7 were each associated with unaligned or lagging chromosomal material, indicating relaxation of spindle checkpoint control. Moreover, by overwhelming checkpoint control mechanisms that may prevent cells with multiple spindle poles to enter anaphase, expression of HPV-16 E6 and E7 leads to a small but significant number of cells with altered polarity at later stages of the cell division process. In addition to changes that have the potential to give rise to numerical chromosome imbalances, we discovered that expression of HPV-16 E7 could trigger anaphase bridge formation to an extent similar to that of high-risk HPV E6. Anaphase bridges typically develop after chromosomal breaks and alterations of chromosomal structure. Further investigation of mechanisms by which HPV-16 E6 and E7 contribute to the destabilization of the host cell genome revealed that both high-risk HPV oncoproteins induce DNA damage. Moreover, expression of HPV-16 E7 was associated with an increased number of cells exhibiting nuclear foci of phosphorylated histone H2AX as well as activation of cell cycle checkpoints triggered by DNA repair. Our results therefore suggest that HPV oncoproteins are a source for both numerical and structural chromosome instability during HPV-associated carcinogenesis.