Differential effects of arsenic(III) and chromium(VI) on nuclear transcription factor binding.
The toxic metals arsenic(III) and chromium(VI) are considered human carcinogens, although they may act through different mechanisms. We previously showed that when administered at single low, non-overtly toxic doses, chromium, arsenic, and several other chemical carcinogens preferentially alter expression of several model inducible genes in both whole-animal and cell-culture systems. In this study, we assessed whether chromium and arsenic target specific signaling pathways within cells to selectively modulate gene expression. We examined the effects of non-cytotoxic and cytotoxic doses of arsenic(III) and chromium(VI) on nuclear binding of the transcription factors AP-1, NF-kappaB, Sp1, and YB-1 in human MDA-MB-435 breast cancer and rat H4IIE hepatoma cells. These transcription factors were chosen because they may regulate many inducible genes, including those previously shown to be altered by metal treatments. We report that both arsenic and chromium significantly altered nuclear binding levels of these factors to their respective cis-acting elements. However, there were qualitative and quantitative differences in these effects that were dependent on the metal, time, dose, transcription factor, and cell line. These effects may play a significant role in metal-induced alterations in gene expression.
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835, USA.
R C
RC
Kaltreider
C A
CA
Pesce
M A
MA
Ihnat
J P
JP
Lariviere
J W
JW
Hamilton
D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002857:Chromium / Q000494:pharmacology*; D017931:DNA Primers; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D014157:Transcription Factors; D002857:Chromium; D001151:Arsenic