Jump to main content
US EPA
United States Environmental Protection Agency
Search
Search
Main menu
Environmental Topics
Laws & Regulations
About EPA
Health & Environmental Research Online (HERO)
Contact Us
Print
Feedback
Export to File
Search:
This record has one attached file:
Add More Files
Attach File(s):
Display Name for File*:
Save
Citation
Tags
HERO ID
1233616
Reference Type
Journal Article
Title
Signal transducer and activator of transcription 1 (STAT1) is essential for chromium silencing of gene induction in human airway epithelial cells
Author(s)
Nemec, AA; Barchowsky, A
Year
2009
Is Peer Reviewed?
1
Journal
Toxicological Sciences
ISSN:
1096-6080
EISSN:
1096-0929
Volume
110
Issue
1
Page Numbers
212-223
Language
English
PMID
19403854
DOI
10.1093/toxsci/kfp084
Web of Science Id
WOS:000267227800019
Abstract
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 extracellular regulated kinase (ERK) signaling cascade that involved Src kinase-activated Sp1 transactivation, as well as increased hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilization and DNA binding. Ni-stimulated ERK, Src, and HIF-1 alpha 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 short hairpin RNA, Cr(VI) increased VEGFA transcript levels and Sp1 transactivation. Moreover, in the absence of STAT1, Cr(VI), and Ni coexposures 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.
Keywords
chromium; nickel; VEGFA; HIF-1 alpha; ERK; Src
Tags
IRIS
•
Chromium VI
Considered
Potentially Relevant Supplemental Material
Mechanistic
Home
Learn about HERO
Using HERO
Search HERO
Projects in HERO
Risk Assessment
Transparency & Integrity