首页> 美国卫生研究院文献>The EMBO Journal >Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in non-tumorigenic and tumorigenic HeLa hybrid cells.
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Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in non-tumorigenic and tumorigenic HeLa hybrid cells.

机译:维甲酸介导的人乳头瘤病毒18转录的抑制和维甲酸受体β基因在非致瘤性和致瘤性HeLa杂交细胞中的不同配体调节。

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摘要

Human papillomavirus type 18 (HPV18) belongs to the group of genital papillomaviruses involved in the development of cervical carcinomas. Since retinoic acid (RA) is a key regulator of epithelial cell differentiation and a growth inhibitor in vitro of HPV18-positive HeLa cervical carcinoma cells, we have used HeLa and HeLa hybrid cells in order to analyse the effects of RA on expression of the HPV18 E6 and E7 oncogenes and of the cellular RA receptor genes RAR-beta and -gamma. We show here that RA down-regulates HPV18 mRNA levels apparently due to transcriptional repression. Transient cotransfection assays indicated that RARs negatively regulate the HPV18 upstream regulatory region and that the central enhancer can confer RA-dependent repression on a heterologous promoter. RA treatment resulted in induction of RAR-beta mRNA levels in non-tumorigenic HeLa hybrid cells, but not in tumorigenic hybrid segregants nor in HeLa cells. No alterations of the RAR-beta gene or of the HeLa RAR-beta promoter could be revealed by Southern and DNA sequence analysis, respectively. As determined by transient transfection assays, however, the RAR-beta control region was activated by RA more strongly in non-tumorigenic hybrid cells than in HeLa cells, thus indicating differences in trans-acting regulatory factors. Our data suggest that the RARs are potential negative regulators of HPV18 E6 and E7 gene expression, and that dysregulation of the RAR-beta gene either causatively contributes to or is an indicator of tumorigenicity in HeLa and HeLa hybrid cells.
机译:18型人乳头瘤病毒(HPV18)属于参与子宫颈癌发展的生殖器乳头瘤病毒。由于视黄酸(RA)是HPV18阳性HeLa宫颈癌细胞体外上皮细胞分化的关键调节剂和体外生长抑制剂,因此我们使用了HeLa和HeLa杂交细胞来分析RA对HPV18表达的影响E6和E7癌基因以及细胞RA受体基因RAR-beta和-gamma。我们在这里显示RA显然由于转录抑制而下调HPV18 mRNA水平。瞬时共转染试验表明,RAR负调控HPV18上游调控区,而中央增强子可以赋予异源启动子RA依赖性阻遏作用。 RA处理可在非致瘤性HeLa杂种细胞中诱导RAR-βmRNA水平,但在致瘤性杂合分离剂和HeLa细胞中均不会。分别通过Southern和DNA序列分析无法揭示RAR-β基因或HeLaRAR-β启动子的变化。但是,通过瞬时转染测定可以确定,非致瘤性杂合细胞中的RAR-β控制区被RA激活的能力比HeLa细胞中强,因此表明反式调节因子的差异。我们的数据表明,RARs是HPV18 E6和E7基因表达的潜在负调控因子,RAR-beta基因的失调可导致HeLa和HeLa杂种细胞致癌,或者是其致癌性指标。

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