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| Status |
Public on Jul 13, 2009 |
| Title |
Coordinate Control of Nrf2 Mediated Genes in the Human Small Airway Epithelium Highly Responsive to Smoking |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) is an oxidant responsive transcription factor known to induce phase 2 detoxifying and antioxidant genes to protect cells from oxidative stress. Cigarette smoke, with its large oxidant content, is a major stressor to the small airway epithelium, the cells of which are vulnerable to oxidant damage and consequent malignant transformation. In this study, we assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample a pure population of small airway epithelium in 38 healthy nonsmokers and 45 healthy smokers, and gene expression was assessed using Affymetrix HG-U133 Plus 2.0 microarrays. Compared to that of healthy nonsmokers, Nrf2 protein was significantly activated in the small airway epithelium of healthy normal smokers and localized in the nucleus (p<0.05). Of the human homologs of 201 known murine Nrf2-mediated genes, 13 highly smoking-responsive genes were identified (p<10-4, all comparisons smokers to nonsmokers). Using a “Nrf2-index” to quantify the extent of expression in the small airway epithelium of these 13 known Nrf2 genes, variability in the level of expression was observed among the 45 healthy smokers, but the variability was coordinately modulated among the 13 genes, an observation confirmed by TaqMan quantitative PCR. This variability in the coordinate level of expression of the 13 Nrf2-mediated genes was independent of the smoking history. Based on these observations, the “Nrf2 index” was used to evaluate whether other genes modulated by smoking in the small airway epithelium were also coordinately up- or down- modulated among the 45 healthy smokers. Two genes, pirin (PIR) and UDP glucuronosyltransferase 1 family polypeptide A4 (UGT1A4), not previously known to be modulated by Nrf2 were identified as being coordinately modulated among the 45 smokers. Both genes contain several functional antioxidant response elements in the promoter region. Using an electrophoretic mobility shift assay, these antioxidant response elements in the promoters of PIR and UGT1A4 responded in vitro to activated Nrf2. These observations are consistent with the concept that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cell population, and that there is variability among the population in the relative Nrf2 responsiveness to a similar oxidant burden.
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| Overall design |
Affymetrix arrays were used to assess gene expression data in small airway epithelium obtained by fiberoptic bronchoscopy of 38 healthy non-smokers and 45 healthy smokers
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| Contributor(s) |
Hübner R, Schwartz JD, De BP, Ferris B, Hackett NR, Crystal RG |
| Citation(s) |
19593404 |
| |
| Submission date |
Jul 01, 2008 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Yael Strulovici-Barel |
| E-mail(s) |
yas2003@med.cornell.edu
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| Organization name |
Weill Cornell Medical College
|
| Department |
Department of Genetic Medicine
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| Lab |
Crystal
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| Street address |
1300 York Avenue
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (83)
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| GSM101095 |
small airways, non-smoker 001, RMA and MAS |
| GSM101096 |
small airways, non-smoker 004, RMA and MAS |
| GSM101097 |
small airways, non-smoker 002, RMA and MAS |
| GSM101098 |
small airways, non-smoker 003, RMA and MAS |
| GSM101100 |
small airways, non-smoker 006, RMA and MAS |
| GSM101101 |
small airways, non-smoker 021, RMA and MAS |
| GSM101102 |
small airways, non-smoker 019, RMA and MAS |
| GSM101103 |
small airways, non-smoker 014, RMA and MAS |
| GSM101104 |
small airways, non-smoker 008, RMA and MAS |
| GSM101105 |
small airways, non-smoker 015, RMA and MAS |
| GSM101106 |
small airways, non-smoker 005, RMA and MAS |
| GSM101109 |
small airways, smoker 027, RMA and MAS |
| GSM101110 |
small airways, smoker 033, RMA and MAS |
| GSM101111 |
small airways, smoker 001, RMA and MAS |
| GSM101113 |
small airways, smoker 048, RMA and MAS |
| GSM101114 |
small airways, smoker 041, RMA and MAS |
| GSM101115 |
small airways, smoker 044, RMA and MAS |
| GSM101116 |
small airways, smoker 049, RMA and MAS |
| GSM114089 |
small airways, smoker 058, MAS5 |
| GSM114090 |
small airways, smoker 063, MAS5 |
| GSM190149 |
Small airways, non-smoker 011 |
| GSM190150 |
Small airways, non-smoker 029 |
| GSM190151 |
small airways, non-smoker 034 |
| GSM190152 |
Small airways, non-smoker 035 |
| GSM190153 |
Small airways, non-smoker 036 |
| GSM190154 |
Small airways, non-smoker 040 |
| GSM190155 |
Small airways, non-smoker 042 |
| GSM190156 |
small airways, non-smoker 044 |
| GSM252871 |
small airways, smoker 040 |
| GSM252876 |
small airways, smoker 057 |
| GSM252878 |
small airways, smoker 069 |
| GSM252879 |
small airways, smoker 074 |
| GSM252880 |
small airways, smoker 093 |
| GSM252881 |
small airways, smoker 094 |
| GSM252882 |
small airways, smoker 095 |
| GSM252884 |
small airways, smoker 098 |
| GSM252885 |
small airways, smoker 103 |
| GSM254149 |
small airways, non-smoker 045 |
| GSM254150 |
small airways, non-smoker 059 |
| GSM254151 |
small airways, non-smoker 071 |
| GSM254152 |
small airways, non-smoker 078 |
| GSM254157 |
small airways, smoker 112 |
| GSM254158 |
small airways, smoker 114 |
| GSM254159 |
small airways, smoker 119 |
| GSM254160 |
small airways, smoker 152 |
| GSM254161 |
small airways, smoker 169 |
| GSM298219 |
small airways, non-smoker 039 |
| GSM298220 |
small airways, non-smoker 046 |
| GSM298221 |
small airways, non-smoker 047 |
| GSM298222 |
small airways, non-smoker 048 |
| GSM298223 |
small airways, non-smoker 050 |
| GSM298224 |
small airways, non-smoker 055 |
| GSM298225 |
small airways, non-smoker 065 |
| GSM298226 |
small airways, non-smoker 072 |
| GSM298227 |
small airways, non-smoker 076 |
| GSM298228 |
small airways, non-smoker 080 |
| GSM298229 |
small airways, non-smoker 083 |
| GSM298230 |
small airways, smoker 087 |
| GSM298231 |
small airways, smoker 102 |
| GSM298232 |
small airways, smoker 120 |
| GSM298233 |
small airways, smoker 122 |
| GSM298234 |
small airways, smoker 123 |
| GSM298235 |
small airways, smoker 125 |
| GSM298236 |
small airways, smoker 129 |
| GSM298237 |
small airways, smoker 130 |
| GSM298238 |
small airways, smoker 134 |
| GSM298239 |
small airways, smoker 136 |
| GSM298240 |
small airways, smoker 141 |
| GSM298241 |
small airways, smoker 155 |
| GSM298242 |
small airways, smoker 159 |
| GSM298243 |
small airways, smoker 161 |
| GSM298244 |
small airways, smoker 164 |
| GSM298245 |
small airways, smoker 167 |
| GSM298246 |
small airways, smoker 176 |
| GSM298247 |
small airways, smoker 177 |
| GSM300859 |
small airways, non-smoker 085 |
| GSM300860 |
small airways, non-smoker 088 |
| GSM300861 |
small airways, smoker 183 |
| GSM302396 |
small airways, non-smoker 022 |
| GSM302397 |
small airways, non-smoker 066 |
| GSM302398 |
small airways, smoker 186 |
| GSM302399 |
small airways, smoker 195 |
| GSM302400 |
small airways, smoker 199 |
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| Relations |
| BioProject |
PRJNA105813 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE11952_RAW.tar |
1.7 Gb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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