PMID- 18629308
OWN - NLM
STAT- MEDLINE
DCOM- 20080912
LR  - 20211020
IS  - 0091-6765 (Print)
IS  - 1552-9924 (Electronic)
IS  - 0091-6765 (Linking)
VI  - 116
IP  - 7
DP  - 2008 Jul
TI  - A novel role of the NRF2 transcription factor in the regulation of 
      arsenite-mediated keratin 16 gene expression in human keratinocytes.
PG  - 873-9
LID - 10.1289/ehp.10696 [doi]
AB  - BACKGROUND: Inorganic sodium arsenite (iAs) is a ubiquitous environmental 
      contaminant and is associated with an increased risk of skin hyperkeratosis and 
      cancer. OBJECTIVES: We investigated the molecular mechanisms underlying the 
      regulation of the keratin 16 (K16) gene by iAs in the human keratinocyte cell 
      line HaCaT. METHODS: We performed reverse transcriptase polymerase chain 
      reaction, luciferase assays, Western blots, and electrophoretic mobility shift 
      assays to determine the transcriptional regulation of the K16 gene by iAs. We 
      used gene overexpression approaches to elucidate the nuclear factor 
      erythroid-derived 2 related factor 2 (NRF2) involved in the K16 induction. 
      RESULTS: iAs induced the mRNA and protein expression of K16. We also found that 
      the expression of K16 was transcriptionally induced by iAs through activator 
      protein-1-like sites and an antioxidant response element (ARE) in its gene 
      promoter region. Treatment with iAs also enhanced the production and 
      translocation of the NRF2 transcription factor, an ARE-binding protein, into the 
      nucleus without modification of its mRNA expression. In addition, iAs elongated 
      the half-life of the NRF2 protein. When overexpressed in HaCaT cells, NRF2 was 
      also directly involved in not only the up-regulation of the detoxification gene 
      thioredoxin but also K16 gene expression. CONCLUSIONS: Our data clearly indicate 
      that the K16 gene is a novel target of NRF2. Furthermore, our findings also 
      suggest that NRF2 has opposing roles in the cell--in the activation of 
      detoxification pathways and in promoting the development of skin disorders.
FAU - Endo, Hitoshi
AU  - Endo H
AD  - Department of Health Science, Asahikawa Medical College, Midorigaoka, Asahikawa, 
      Hokkaido, Japan.
FAU - Sugioka, Yoshihiko
AU  - Sugioka Y
FAU - Nakagi, Yoshihiko
AU  - Nakagi Y
FAU - Saijo, Yasuaki
AU  - Saijo Y
FAU - Yoshida, Takahiko
AU  - Yoshida T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 0 (Arsenites)
RN  - 0 (KRT16 protein, human)
RN  - 0 (Keratin-16)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sodium Compounds)
RN  - 48OVY2OC72 (sodium arsenite)
SB  - IM
MH  - Arsenites/*toxicity
MH  - Cell Line
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression
MH  - Humans
MH  - Keratin-16/*biosynthesis/genetics
MH  - Keratinocytes/*drug effects/metabolism
MH  - NF-E2-Related Factor 2/*physiology
MH  - RNA, Messenger/biosynthesis
MH  - Sodium Compounds/*toxicity
MH  - Transcriptional Activation
PMC - PMC2453154
OTO - NOTNLM
OT  - antioxidant response element
OT  - arsenic
OT  - hyperkeratosis
OT  - keratin 16 (K16)
OT  - keratinocytes
OT  - nuclear factor erythroid-derived 2 related factor 2 (NRF2)
OT  - transcription
EDAT- 2008/07/17 09:00
MHDA- 2008/09/16 09:00
PMCR- 2008/07/01
CRDT- 2008/07/17 09:00
PHST- 2007/07/20 00:00 [received]
PHST- 2008/03/06 00:00 [accepted]
PHST- 2008/07/17 09:00 [pubmed]
PHST- 2008/09/16 09:00 [medline]
PHST- 2008/07/17 09:00 [entrez]
PHST- 2008/07/01 00:00 [pmc-release]
AID - ehp0116-000873 [pii]
AID - 10.1289/ehp.10696 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2008 Jul;116(7):873-9. doi: 10.1289/ehp.10696.