Dioxin-induced immortalization of normal human keratinocytes and silencing of p53 and p16INK4a.
Dioxin, a potent tumor promoter, activates the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor belonging to the basic helix-loop-helix-PAS family, to enhance tumorigenesis via unknown mechanisms. We undertook this study to determine the mechanisms underlying the impact of dioxin on cell fate, in particular senescence that occurs in normal human cells and is considered to play important tumor suppressive function. We have previously shown that in primary human keratinocytes, dioxin attenuates senescence while retaining the proliferative capacity and represses expression of the tumor suppressors, p16(INK4a) and p53. Here, we show that repression of p16(INK4a) and p53 transcriptional activity by dioxin absolutely requires the AHR and is accompanied by promoter methylation. Furthermore, dioxin alone is sufficient to immortalize normal human keratinocytes. Our data introduce a previously unrecognized regulatory pathway, that of the AHR, that impacts senescence. More importantly, this is the first report of a tumor promoter capable of inhibiting senescence in a receptor mediated manner and introduces a novel mechanism by which this carcinogen may contribute to human malignancies.
Ray
Soma S
SS
Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Swanson
Hollie I
HI
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D016227:Benzoquinones; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011809:Quinones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
C091768:3'-methoxy-4'-nitroflavone; C497396:ARNT protein, human; D016227:Benzoquinones; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D005419:Flavonoids; D047029:Lactams, Macrocyclic; D000072317:Polychlorinated Dibenzodioxins; D011809:Quinones; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004247:DNA; C001277:geldanamycin