title: Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential.
abstract: Previous work has suggested that arsenic exposure contributes to skin carcinogenesis by preserving the proliferative potential of human epidermal keratinocytes, thereby slowing the exit of putative target stem cells into the differentiation pathway. To find a molecular basis for this action, present work has explored the influence of arsenite on keratinocyte responses to epidermal growth factor (EGF). The ability of cultured keratinocytes to found colonies upon passaging several days after confluence was preserved by arsenite and EGF in an additive fashion, but neither was effective when the receptor tyrosine kinase activity was inhibited. Arsenite prevented the loss of EGF receptor protein and phosphorylation of tyrosine 1173, preserving its capability to signal. The level of nuclear beta-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative beta-catenin suppressed the increase in both colony forming ability and yield of putative stem cells induced by arsenite and EGF. As judged by expression of three genes regulated by beta-catenin, this transcription factor had substantially higher activity in the arsenite/EGF-treated cells. Trivalent antimony exhibited the same effects as arsenite. A novel finding is that insulin in the medium induced the loss of EGF receptor protein, which was largely prevented by arsenite exposure.
authors.affiliation: Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA 95616-8588, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Patterson
authors.forename: Robert H
authors.initials: RH
authors.lastname: Rice
mesh_terms: D000965:Antimony / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; D018053:Arsenites; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D047494:PPAR delta; D011743:Pyrimidines; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; D051176:beta Catenin; C101044:RTKI cpd; C061374:antimonite; D004815:Epidermal Growth Factor; D003513:Cycloheximide; D000965:Antimony; D066246:ErbB Receptors; D020783:Matrix Metalloproteinase 7; D018631:ras Proteins