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.
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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视黄酸介导的人乳头瘤病毒 18 转录抑制以及非致瘤性和致瘤性 HeLa 杂交细胞中视黄酸受体 β 基因的不同配体调节。
DOI：
10.1002/j.1460-2075.1992.tb05287.x
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Elisabeth Schwarz
中科院分区：
文献类型：
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作者：
Dusan Bartsch;Barbara Boye;C. Baust;H. Z. Hausen;Elisabeth Schwarz
人乳头瘤病毒18型（HPV18）属于生殖器乳头瘤病毒群，参与宫颈癌的发展。由于维甲酸（RA）是体外HPV18阳性HeLa宫颈癌细胞上皮细胞分化的关键调节剂和生长抑制剂，我们使用HeLa和HeLa杂交细胞来分析RA对HPV18 E6和E7癌基因以及细胞RA受体基因RAR - β和- γ表达的影响。我们在这里表明，由于转录抑制，RA明显下调HPV18 mRNA水平。瞬时共转染实验表明，RARs负向调控HPV18上游调控区，中心增强子可以对异源启动子施加RA依赖的抑制。RA治疗在非致瘤性HeLa杂交细胞中诱导RAR - β mRNA水平，但在致瘤性杂交分离细胞和HeLa细胞中没有诱导RAR - β mRNA水平。DNA序列分析和Southern分析均未发现RAR - β基因和HeLa RAR - β启动子的变化。然而，瞬时转染实验表明，与HeLa细胞相比，非致瘤性杂交细胞中的RAR - β控制区被RA激活的程度更强，这表明反式作用调节因子存在差异。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 - β基因的失调可能是HeLa和HeLa杂交细胞致瘤性的原因，也可能是致瘤性的一个指标。
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.