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 β-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative β-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 β-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 119-128 |
| Number of pages | 10 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 221 |
| Issue number | 1 |
| DOIs | |
| State | Published - May 15 2007 |
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Keywords
- β-catenin
- Antimony
- Arsenite
- Epidermal growth factor
- Insulin
- Keratinocyte
ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. / Patterson, Timothy J.; Rice, Robert H.
In: Toxicology and Applied Pharmacology, Vol. 221, No. 1, 15.05.2007, p. 119-128.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential
AU - Patterson, Timothy J.
AU - Rice, Robert H.
PY - 2007/5/15
Y1 - 2007/5/15
N2 - 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 β-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative β-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 β-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.
AB - 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 β-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative β-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 β-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.
KW - β-catenin
KW - Antimony
KW - Arsenite
KW - Epidermal growth factor
KW - Insulin
KW - Keratinocyte
UR - http://www.scopus.com/inward/record.url?scp=34247887332&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247887332&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2007.02.003
DO - 10.1016/j.taap.2007.02.003
M3 - Article
C2 - 17400267
AN - SCOPUS:34247887332
VL - 221
SP - 119
EP - 128
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1
ER -