RNA splicing factors regulated by HPV16 during cervical tumour progression.
RNA splicing factors regulated by HPV16 during cervical tumour progression.
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DOI：
10.1002/path.2608
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Graham SV
中科院分区：
文献类型：
--
作者：
Mole S;McFarlane M;Chuen-Im T;Milligan SG;Millan D;Graham SV
引起宫颈疾病的最普遍的人乳头瘤病毒（HPV）是“高危”HPV 16和18型。所有乳头瘤病毒都表达一种转录因子E2，它可以调节病毒和细胞基因的表达。最近，我们证明了高危型HPV E2介导的SF 2/ASF的转录反式激活。这种必需的癌蛋白是调节组成性和选择性剪接的SR蛋白家族的关键成员。RNA剪接的严格控制对于野生型蛋白质的产生是必要的。因此，SR蛋白的异常表达与包括癌症在内的一系列人类疾病的病因学有关。在这里，我们证明了上皮分化特异性控制SF 2/ASF在HPV 16感染的角质形成细胞在器官型筏培养和低度宫颈病变（CIN 1）。此外，我们证明了HPV 16感染/分化诱导的SR蛋白的特定子集的上调，并提出证据表明HPV 16 E2控制SRp 20，SC 35和SRp 75的表达。使用一系列宫颈肿瘤进展模型的细胞系，我们显示SF 2/ASF，SRp 20和SC 35在宫颈肿瘤进展模型中特异性上调。这些SR蛋白在高级别宫颈病变中也过表达，表明它们可能都具有致癌功能。SR蛋白可能是HPV相关疾病的有用生物标志物。
The most prevalent human papillomaviruses (HPVs) causing cervical disease are the “high risk” HPV types 16 and 18. All papillomaviruses express a transcription factor, E2 that can regulate viral and cellular gene expression. Recently, we demonstrated high risk HPV E2-mediated transcriptional transactivation of SF2/ASF. This essential oncoprotein is a key member of a family of proteins, the SR proteins that regulate constitutive and alternative splicing. Tight control of RNA splicing is necessary for production of wild type proteins. So, aberrant expression of SR proteins is involved in the aetiology of a range of human diseases, including cancer. Here we demonstrate epithelial differentiation-specific control of SF2/ASF in HPV16 infected keratinocytes in organotypic raft culture and in low grade cervical lesions (CIN1). Further, we demonstrate HPV16 infection/differentiation-induced up-regulation of a specific subset of SR proteins and present evidence that HPV16 E2 controls expression of SRp20, SC35 and SRp75. Using a series of cell lines that model cervical tumour progression we show SF2/ASF, SRp20 and SC35 are specifically up-regulated in a model of cervical tumour progression. These SR proteins are also overexpressed in high grade cervical lesions, indicating that they may all have oncogenic functions. SR proteins could be useful biomarkers for HPV-associated disease.
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