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 language | English (US) |
|---|---|
| Pages (from-to) | 302-311 |
| Number of pages | 10 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 174 |
| Issue number | 3 |
| DOIs | |
| State | Published - Aug 1 2001 |
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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 journal › Article
}
TY - JOUR
T1 - Keratinocyte differentiation marker suppression by arsenic
T2 - Mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate
AU - Jessen, Bart A.
AU - Qin, Qin
AU - Phillips, Marjorie A.
AU - Phillips, Donald L.
AU - Rice, Robert H.
PY - 2001/8/1
Y1 - 2001/8/1
N2 - 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.
AB - 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.
KW - AP1
KW - Epidermis
KW - Involucrin
KW - TGM1
KW - TPA
UR - http://www.scopus.com/inward/record.url?scp=0035419708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035419708&partnerID=8YFLogxK
U2 - 10.1006/taap.2001.9227
DO - 10.1006/taap.2001.9227
M3 - Article
C2 - 11485391
AN - SCOPUS:0035419708
VL - 174
SP - 302
EP - 311
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 3
ER -