Ethanol upregulates the expression of p21 WAF1/CIP1 and prolongs G1 transition via a p53-independent pathway in human epithelial cells.
The control of cell cycle progression is necessary for accuracy in the replication of DNA and the distribution of genetic information to daughter cells. Disturbances in progression of the cell cycle may result in the loss of genomic integrity, a 'hallmark' of cancer cells. Extensive consumption of alcoholic beverages is a risk factor associated with the development of various human epidermoid cancer including oral and pharyngeal squamous cell carcinomas. However, effects of ethanol on cell cycle progression and on the expression of genes associated with the cell cycle have not been studied. We report here that exposure of human epithelial cells to ethanol, at concentration (100-200 mM) that do not cause cell death, (a) does not affect or only reduces slightly the cellular level of p53 protein, (b) upregulates the transcription of the WAF1/CIP1 gene, (c) inhibits the Cdk2 activity, and (d) reduces the rate of cellular proliferation by inducing a delay in G1 phase transition. The results also indicate that, at these non-cytotoxic concentrations, ethanol exhibits its effects through a p53-independent mechanism.
Guo
W
W
Dental Research Institute, University of California, Los Angeles 90095-1668, USA.
Baluda
M A
MA
Park
N H
NH
D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics*; D004847:Epithelial Cells; D000431:Ethanol / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D000097642:GADD45 Proteins
D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D000431:Ethanol; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human; C495894:CDK2 protein, human