Zhao Xiaomin, Fay Joanna, Lambkin Helen, Schwartz Stefan
Department of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, Husargatan 3, Box 582, 751 23 Uppsala, Sweden.
Virology. 2007 Dec 20;369(2):351-63. doi: 10.1016/j.virol.2007.08.002. Epub 2007 Sep 14.
Human papillomavirus type 16 (HPV-16) infections can in rare cases persist and cause lesions that may progress to cervical cancer. Cells in the lesions are not permissive for virus production, nor are cervical cancer cells. The intracellular environment is such that it prevents production of the highly immunogenic, viral structural proteins L1 and L2. One may speculate that inhibition of L1 and L2 expression is a prerequisite for persistence and cancer progression. We have therefore investigated how expression of HPV-16 L1 is regulated. We found that the only splice site in the HPV-16 late region, which is used to produce L1 mRNAs, is under control of a splicing enhancer located in the 17 nucleotides immediately downstream of the splice site. However, the function of this enhancer in cervical cancer cells is largely overshadowed by multiple splicing silencers in the late region which bind to hnRNP A1. High levels of hnRNP A1 therefore inhibit HPV-16 L1 expression. Immunohistological analysis of cervical epithelia revealed that hnRNP A1 is expressed primarily in the lower layers of the epithelium. hnRNP A1 is undetectable in terminally differentiated cells that can express HPV-16 late genes, which supports the conclusion that high levels of hnRNP A1 inhibit HPV-16 L1 expression.
16型人乳头瘤病毒（HPV - 16）感染在极少数情况下会持续存在，并引发可能发展为宫颈癌的病变。病变中的细胞不允许病毒产生，宫颈癌细胞也是如此。细胞内环境使得高度免疫原性的病毒结构蛋白L1和L2无法产生。有人推测，抑制L1和L2的表达是病毒持续存在和癌症进展的先决条件。因此，我们研究了HPV - 16 L1的表达是如何调控的。我们发现，HPV - 16晚期区域中用于产生L1 mRNA的唯一剪接位点受位于该剪接位点下游紧邻的17个核苷酸处的一个剪接增强子的控制。然而，在晚期区域中多个与hnRNP A1结合的剪接沉默子在很大程度上掩盖了该增强子在宫颈癌细胞中的功能。因此，高水平的hnRNP A1会抑制HPV - 16 L1的表达。对宫颈上皮的免疫组织学分析显示，hnRNP A1主要在上皮的下层表达。在能够表达HPV - 16晚期基因的终末分化细胞中检测不到hnRNP A1，这支持了高水平的hnRNP A1抑制HPV - 16 L1表达这一结论。
