Beniston Richard Garry, Campo Maria Saveria
Institute of Comparative Medicine, Glasgow University Veterinary School, Garscube Estate, Glasgow G61 1QH, Scotland, UK.
Oncogene. 2003 Aug 21;22(35):5504-14. doi: 10.1038/sj.onc.1206848.
Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the development of tumorigenic cells lines (Beniston et al., 2001). Given the possible link between papillomavirus infection, bracken fern in the diet and cancer of the upper gastrointestinal (GI) tract in humans, we investigated whether a similar situation would occur in human cells transformed by human papillomavirus type 16 (HPV-16) oncoproteins. Quercetin arrested primary human foreskin keratinocytes in G1. Arrest was linked to an elevation of the cyclin-dependent kinase inhibitor (cdki) p27(Kip1). Expression of the HPV16 E6 and E7 oncoproteins in transformed cells failed to abrogate cell cycle arrest. G1 arrest in the transformed cells was also linked to an increase of p27(Kip1) with a concomitant reduction of cyclin E-associated kinase activity. This elevation of p27(Kip1) was due not only to increased protein half-life, but also to increased mRNA transcription.
我们之前对原代牛成纤维细胞的研究表明，槲皮素是蕨菜（Pteridium aquilinum）中含量很高的一种强效诱变剂，它会使细胞停滞在G1期和G2/M期，这与p53激活相关。牛乳头瘤病毒4型（BPV-4）E7的表达克服了这种停滞，并导致致瘤细胞系的产生（贝尼斯顿等人，2001年）。鉴于乳头瘤病毒感染、饮食中的蕨菜与人类上消化道（GI）癌症之间可能存在联系，我们研究了在由人乳头瘤病毒16型（HPV-16）癌蛋白转化的人类细胞中是否会出现类似情况。槲皮素使原代人包皮角质形成细胞停滞在G1期。停滞与细胞周期蛋白依赖性激酶抑制剂（cdki）p27（Kip1）的升高有关。转化细胞中HPV16 E6和E7癌蛋白的表达未能消除细胞周期停滞。转化细胞中的G1期停滞也与p27（Kip1）的增加以及细胞周期蛋白E相关激酶活性的相应降低有关。p27（Kip1）的这种升高不仅是由于蛋白质半衰期延长，还由于mRNA转录增加。
