Quercetin elevates p27(Kip1) and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1.
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.
Beniston
Richard Garry
RG
Institute of Comparative Medicine, Glasgow University Veterinary School, Garscube Estate, Glasgow G61 1QH, Scotland, UK.
Campo
Maria Saveria
MS
D018797:Cell Cycle Proteins / Q000187:drug effects*; D002461:Cell Line, Transformed; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D009153:Mutagens / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000187:drug effects*; D050725:Papillomavirus E7 Proteins; D032498:Pteridium / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins / Q000187:drug effects*
D018797:Cell Cycle Proteins; C068651:E6 protein, Human papillomavirus type 16; D009153:Mutagens; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011794:Quercetin