Keratinocyte differentiation marker suppression by arsenic: mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate.
Culture models of target cells are anticipated to help elucidate the mechanism by which inorganic arsenic acts as a carcinogen in humans. Present work characterizes the response of human keratinocytes, a target cell type, to arsenic suppression of their differentiation program. Four representative differentiation marker mRNAs (involucrin, keratinocyte transglutaminase, small proline-rich protein 1, and filaggrin) were suppressed by both arsenate and arsenite in normal, spontaneously immortalized (premalignant), and malignant keratinocytes with EC50 values in the low micromolar range. The suppression was almost completely reversed 9 days after removal of arsenate from the culture medium. In the case of the involucrin gene, suppression was mediated primarily by two functional AP1 response elements in the gene promoter. Both glucocorticoid and serum stimulation of differentiation occurred to a similar extent in the presence and absence of arsenic, indicating neither stimulation was a specific target of arsenic action and neither agent could overcome arsenic suppression. In contrast, 12-O-tetradecanoylphorbol-13-acetate prevented the suppression of keratinocyte transglutaminase, suggesting that arsenic acts upstream of protein kinase C.
Jessen
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BA
Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, California, 95616-8588, USA.
Qin
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Q
Phillips
M A
MA
Phillips
D L
DL
Rice
R H
RH
D001149:Arsenates / Q000494:pharmacology; D001151:Arsenic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation; D000091344:Filaggrin Proteins; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D016015:Logistic Models; D010750:Phosphoproteins / Q000378:metabolism*; D011498:Protein Precursors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D011503:Transglutaminases / Q000096:biosynthesis
D001149:Arsenates; D018053:Arsenites; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C417942:Krtdap protein, rat; D010750:Phosphoproteins; D011498:Protein Precursors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C032253:involucrin; D011503:Transglutaminases; C105804:transglutaminase 1; C015001:arsenite; D001151:Arsenic; C025657:arsenic acid; D013755:Tetradecanoylphorbol Acetate