Keratinocyte differentiation marker suppression by arsenic

Mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate

Bart A. Jessen, Qin Qin, Marjorie A. Phillips, Donald L. Phillips, Robert H. Rice

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 prolinerich 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.

Original languageEnglish (US)
Pages (from-to)302-311
Number of pages10
JournalToxicology and Applied Pharmacology
Volume174
Issue number3
DOIs
StatePublished - Aug 1 2001

Fingerprint

Differentiation Antigens
Arsenic
Response Elements
Tetradecanoylphorbol Acetate
Keratinocytes
Transglutaminases
Genes
Carcinogens
Protein Kinase C
Glucocorticoids
Culture Media
Acetates
Messenger RNA
Serum
Proteins

Keywords

  • AP1
  • Epidermis
  • Involucrin
  • TGM1
  • TPA

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Keratinocyte differentiation marker suppression by arsenic : Mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate. / Jessen, Bart A.; Qin, Qin; Phillips, Marjorie A.; Phillips, Donald L.; Rice, Robert H.

In: Toxicology and Applied Pharmacology, Vol. 174, No. 3, 01.08.2001, p. 302-311.

Research output: Contribution to journalArticle

Jessen, Bart A. ; Qin, Qin ; Phillips, Marjorie A. ; Phillips, Donald L. ; Rice, Robert H. / Keratinocyte differentiation marker suppression by arsenic : Mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate. In: Toxicology and Applied Pharmacology. 2001 ; Vol. 174, No. 3. pp. 302-311.
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