Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes
Zhao, R; Hou, Y; Xue, P; Woods, CG; Fu, J; Feng, B; Guan, D; Sun, G; Chan, JY; Waalkes, MP; Andersen, ME; Pi, J
HERO ID
710976
Reference Type
Journal Article
Year
2011
Language
English
PMID
| HERO ID | 710976 |
|---|---|
| In Press | No |
| Year | 2011 |
| Title | Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes |
| Authors | Zhao, R; Hou, Y; Xue, P; Woods, CG; Fu, J; Feng, B; Guan, D; Sun, G; Chan, JY; Waalkes, MP; Andersen, ME; Pi, J |
| Journal | Environmental Health Perspectives |
| Volume | 119 |
| Issue | 1 |
| Page Numbers | 56-62 |
| Abstract | Human exposure to inorganic arsenic (iAs), a potent oxidative stressor, causes various dermal disorders, including hyperkeratosis and skin cancer. Nuclear factor-erythroid 2-related factor 1 (NRF1, also called NFE2L1) plays a critical role in regulating the expression of many antioxidant response element (ARE)-dependent genes.<br /><br /> We investigated the role of NRF1 in arsenic-induced antioxidant response and cytotoxicity in human keratinocytes.<br /><br /> In cultured human keratinocyte HaCaT cells, inorganic arsenite (iAs3+) enhanced the protein accumulation of long isoforms (120-140 kDa) of NRF1 in a dose- and time-dependent fashion. These isoforms accumulated mainly in the nuclei of HaCaT cells. Selective deficiency of NRF1 by lentiviral short-hairpin RNAs in HaCaT cells [NRF1-knockdown (KD)] led to decreased expression of γ-glutamate cysteine ligase catalytic subunit (GCLC) and regulatory subunit (GCLM) and a reduced level of intracellular glutathione. In response to acute iAs3+ exposure, induction of some ARE-dependent genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), GCLC, and GCLM, was significantly attenuated in NRF1-KD cells. However, the iAs3-induced expression of heme oxygenase 1 (HMOX-1) was unaltered by silencing NRF1, suggesting that HMOX-1 is not regulated by NRF1. In addition, the lack of NRF1 in HaCaT cells did not disturb iAs3+-induced NRF2 accumulation but noticeably decreased Kelch-like ECH-associated protein 1 (KEAP1) levels under basal and iAs3+-exposed conditions, suggesting a potential interaction between NRF1 and KEAP1. Consistent with the critical role of NRF1 in the transcriptional regulation of some ARE-bearing genes, knockdown of NRF1 significantly increased iAs3+-induced cytotoxicity and apoptosis.<br /><br /> Here, we demonstrate for the first time that long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes and protect the cells from acute arsenic cytotoxicity. |
| Doi | 10.1289/ehp.1002304 |
| Pmid | 20805060 |
| Wosid | WOS:000285788900024 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | |WOS:000285788900024 |
| Is Public | Yes |
| Language Text | English |
| Keyword | apoptosis; arsenic; cytotoxicity; KEAP1; keratinocyte; NRF1; NRF2; oxidative stress |
| Is Qa | No |