ToxSci Advance Access published online on April 29, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp084
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Signal transducer and activator of transcription 1 (STAT1) is essential for chromium silencing of gene induction in human airway epithelial cells
Department of Environmental and Occupational Health, University of Pittsburgh, Bridgeside Point Bldg. 100 Technology Dr., Ste. 350, Pittsburgh, PA 15219
Corresponding Author: Aaron Barchowsky, Ph.D., Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Bridgeside Point Building, 100 Technology Dr., Room 332, Pittsburgh, PA 15219-3130, USA, Tel.: 412-624-8864, Fax: 412-624-9361, E-mail: aab20{at}pitt.edu
Received March 13, 2009; revision received April 16, 2009; accepted April 17, 2009
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Abstract |
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Hexavalent chromium (Cr(VI)) promotes lung injury and pulmonary diseases through poorly defined mechanisms that may involve the silencing of inducible protective genes. The current study investigated the hypothesis that Cr(VI) actively signals through a signal transducer and activator of transcription 1 (STAT1)-dependent pathway to silence nickel (Ni)-induced expression of vascular endothelial cell growth factor A (VEGFA), an important mediator of lung injury and repair. In human bronchial airway epithelial (BEAS-2B) cells, Ni induced VEGFA transcription by stimulating an ERK signaling cascade that involved Src kinase-activated Sp1 transactivation, as well as increased hypoxia-inducible factor-1
(HIF-1) stabilization and DNA binding. Ni-stimulated ERK, Src, and HIF-1 activities, as well as Ni-induced VEGFA transcript levels were inhibited in Cr(VI) exposed cells. We previously demonstrated that Cr(VI) stimulates STAT1 to suppress VEGFA expression. In BEAS-2B cells stably expressing STAT1 shRNA, Cr(VI) increased VEGFA transcript levels and Sp1 transactivation. Moreover, in the absence of STAT1, Cr(VI) and Ni co-exposures positively interacted to further increase VEGFA transcripts. This study demonstrates that metal-stimulated signaling cascades interact to regulate transcription and induction of adaptive or repair responses in airway cells. In addition, the data implicate STAT1 as a rate limiting mediator of Cr(VI)-stimulated gene regulation and suggest that cells lacking STAT1, such as many tumor cell lines, have opposite responses to Cr(VI) relative to normal cells.
Key Words: chromium; nickel; VEGFA; HIF-1; ERK; Src.