Clonal selection for transcriptionally active viral oncogenes during progression to cancer
Clonal selection for transcriptionally active viral oncogenes during progression to cancer
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DOI：
10.1128/jvi.78.20.11172-11186.2004
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发表时间：
2004-10-01
影响因子：
5.4
通讯作者：
Chow, LT
中科院分区：
文献类型：
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作者：
Van Tine, BA;Kappes, JC;Chow, LT
人乳头瘤病毒（HPVs）永生化的原代角质形成细胞以及HPV诱导的宫颈癌细胞系是研究肿瘤向癌症进展的极佳模型。通过同时观察间期核中的病毒DNA和新生病毒转录本，我们首次证明了对单个优势乳头瘤病毒转录中心或区域（PVTD）的选择，该选择与整合的病毒DNA拷贝数或基因座无关。PVTD与几个已知的亚核区域无关联，但几乎总是位于核仁周边。病毒基因组的沉默拷贝可通过在DNA甲基化抑制剂5 - 氮杂胞苷中生长而被激活。用HPV致癌基因超转导并筛选出标记基因共表达的HPV永生化角质形成细胞经历了危机，存活的细胞仅转录新引入的基因。因此，响应环境变化的转录选择是一个动态过程，可实现细胞存活的最佳基因表达。这种现象在癌症发生过程中的克隆选择中可能至关重要。对HPV相关癌症的检查支持这一假设。
Primary keratinocytes immortalized by human papillomaviruses (HPVs), along with HPV-induced cervical carcinoma cell lines, are excellent models for investigating neoplastic progression to cancer. By simultaneously visualizing viral DNA and nascent viral transcripts in interphase nuclei, we demonstrated for the first time a selection for a single dominant papillomavirus transcription center or domain (PVTD) independent of integrated viral DNA copy numbers or loci. The PVTD did not associate with several known subnuclear addresses but was almost always perinucleolar. Silent copies of the viral genome were activated by growth in the DNA methylation inhibitor 5-azacytidine. HPV-immortalized keratinocytes supertransduced with HPV oncogenes and selected for marker gene coexpression underwent crisis, and the surviving cells transcribed only the newly introduced genes. Thus, transcriptional selection in response to environmental changes is a dynamic process to achieve optimal gene expression for cell survival. This phenomenon may be critical in clonal selection during carcinogenesis. Examination of HPV-associated cancers supports this hypothesis.