PMID- 22476201
OWN - NLM
STAT- MEDLINE
DCOM- 20120731
LR  - 20240506
IS  - 1552-9924 (Electronic)
IS  - 0091-6765 (Print)
IS  - 0091-6765 (Linking)
VI  - 120
IP  - 4
DP  - 2012 Apr
TI  - Cross-regulations among NRFs and KEAP1 and effects of their silencing on 
      arsenic-induced antioxidant response and cytotoxicity in human keratinocytes.
PG  - 583-9
LID - 10.1289/ehp.1104580 [doi]
AB  - BACKGROUND: Nuclear factor E2-related factors (NRFs), including NRF2 and NRF1, 
      play critical roles in mediating the cellular adaptive response to oxidative 
      stress. Human exposure to inorganic arsenic, a potent oxidative stressor, causes 
      various dermal disorders, including hyperkeratosis and skin cancer. OBJECTIVE: We 
      investigated the cross-regulations among NRF2, NRF1, and KEAP1, a 
      cullin-3-adapter protein that allows NRF2 to be ubiquinated and degraded by the 
      proteasome complex, in arsenic-induced antioxidant responses. RESULTS: In human 
      keratinocyte HaCaT cells, selective knockdown (KD) of NRF2 by lentiviral short 
      hairpin RNAs (shRNAs) significantly reduced the expression of many antioxidant 
      enzymes and sensitized the cells to acute cytotoxicity of inorganic arsenite 
      (iAs(3+)). In contrast, silencing KEAP1 led to a dramatic resistance to 
      iAs(3+)-induced apoptosis. Pretreatment of HaCaT cells with NRF2 activators, such 
      as tert-butylhydroquinone, protects the cells against acute iAs(3+) toxicity in 
      an NRF2-dependent fashion. Consistent with the negative regulatory role of KEAP1 
      in NRF2 activation, KEAP1-KD cells exhibited enhanced transcriptional activity of 
      NRF2 under nonstressed conditions. However, deficiency in KEAP1 did not 
      facilitate induction of NRF2-target genes by iAs(3+). In addition, NRF2 silencing 
      reduced the expression of KEAP1 at transcription and protein levels but increased 
      the protein expression of NRF1 under the iAs(3+)-exposed condition. In contrast, 
      silencing KEAP1 augmented protein accumulation of NRF2 under basal and 
      iAs3+-exposed conditions, whereas the iAs(3+)-induced protein accumulation of 
      NRF1 was attenuated in KEAP1-KD cells. CONCLUSIONS: Our studies suggest that 
      NRF2, KEAP1, and NRF1 are coordinately involved in the regulation of the cellular 
      adaptive response to iAs(3+)-induced oxidative stress.
FAU - Zhao, Rui
AU  - Zhao R
AD  - School of Forensic Medicine, China Medical University, Shenyang, China.
FAU - Hou, Yongyong
AU  - Hou Y
FAU - Zhang, Qiang
AU  - Zhang Q
FAU - Woods, Courtney G
AU  - Woods CG
FAU - Xue, Peng
AU  - Xue P
FAU - Fu, Jingqi
AU  - Fu J
FAU - Yarborough, Kathy
AU  - Yarborough K
FAU - Guan, Dawei
AU  - Guan D
FAU - Andersen, Melvin E
AU  - Andersen ME
FAU - Pi, Jingbo
AU  - Pi J
LA  - eng
GR  - R01 ES016005/ES/NIEHS NIH HHS/United States
GR  - ES016005/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120103
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 0 (Antioxidants)
RN  - 0 (Arsenites)
RN  - 0 (Environmental Pollutants)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sodium Compounds)
RN  - 48OVY2OC72 (sodium arsenite)
RN  - N712M78A8G (Arsenic)
SB  - IM
MH  - Antioxidants/*metabolism
MH  - Apoptosis
MH  - Arsenic/*pharmacology
MH  - Arsenites/pharmacology
MH  - Blotting, Western
MH  - Cell Line
MH  - Dose-Response Relationship, Drug
MH  - Environmental Pollutants/*toxicity
MH  - Flow Cytometry
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Kelch-Like ECH-Associated Protein 1
MH  - Keratinocytes/cytology/*drug effects/physiology
MH  - Lentivirus
MH  - NF-E2-Related Factor 1/genetics/*metabolism
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Oxidative Stress
MH  - RNA, Small Interfering/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Skin Diseases/chemically induced/physiopathology
MH  - Sodium Compounds/pharmacology
PMC - PMC3339469
COIS- The content is solely the responsibility of the authors. All authors have agreed 
      to its content. M.E.A. received some funding from Dow Chemical Company. All of 
      the other authors declare they have no actual or potential competing financial 
      interests.
EDAT- 2012/04/06 06:00
MHDA- 2012/08/01 06:00
PMCR- 2012/04/01
CRDT- 2012/04/06 06:00
PHST- 2011/10/04 00:00 [received]
PHST- 2012/01/03 00:00 [accepted]
PHST- 2012/04/06 06:00 [entrez]
PHST- 2012/04/06 06:00 [pubmed]
PHST- 2012/08/01 06:00 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - ehp.1104580 [pii]
AID - 10.1289/ehp.1104580 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2012 Apr;120(4):583-9. doi: 10.1289/ehp.1104580. Epub 
      2012 Jan 3.