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Arsenite Induces a Cell Stress-Response Gene, RTP801, Through Reactive Oxygen Species and Transcription Factors Elk-1 and CCAAT/Enhancer-Binding Protein

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  • Personal Author:
  • Description:
    RTP801 is a newly discovered stress-response gene that is induced by hypoxia and other cell stress signals. Arsenic is a heavy metal that is linked to carcinogenesis in humans. Here, we investigated the mechanism by which arsenic induces RTP801 transcription. In HaCaT human keratinocytes, arsenite was able to induce a rapid rise in the RTP801 mRNA level. Correspondingly, arsenite treatment was capable of stimulating a 2.5 kb human RTP801 promoter. Such a stimulatory effect was inhibited by co-expression of superoxide dismutase or glutathione peroxidase, and was abrogated by N-acetylcysteine, implying that ROS (reactive oxygen species) were involved in transcriptional regulation of the RTP801 gene. A series of deletion studies with the promoter revealed a critical arsenic-responsive region between -1057 and -981 bp of the promoter. Point mutations of the putative Elk-1 site and the C/EBP (CCAAT/enhancer-binding protein) site within this region were able to reduce the stimulatory effect of arsenite, indicating that Elk-1 and C/EBP are involved in transcriptional regulation of the RTP801 gene by arsenite. Furthermore, a gel mobility-shift assay demonstrated that arsenite was able to mount the rapid formation of a protein complex that bound the arsenic-responsive region as well as the C/EBP-containing sequence. The arsenite stimulation on RTP801 transcription was partly mediated by the ERK (extracellular-signal-regulated kinase) pathway, since the effect of RTP801 was inhibited by a selective ERK inhibitor. In addition, overexpression of Elk-1 and C/EBPbeta was able to elevate the promoter activity. Therefore these studies indicate that RTP801 is a transcriptional target of arsenic in human keratinocytes, and that arsenic and ROS production are linked to Elk-1 and C/EBP in the transcriptional control. [Description provided by NIOSH]
  • Subjects:
  • Keywords:
  • ISSN:
    0264-6021
  • Document Type:
    Text
  • Genre:
    Journal Article
  • Place as Subject:
  • CIO:
    National Institute for Occupational Safety and Health (NIOSH)
  • Division:
    HELD - Health Effects Laboratory Division
  • Topic:
    Workplace Safety & Health
  • Location:
    North America
  • Pages in Document:
    93-102
  • Volume:
    392
  • NIOSHTIC Number:
    nn:20028984
  • Citation:
    Biochem J 2005 Nov; 392(Pt 1):93-102
  • Email:
    ychen3@iupui.edu
  • CAS Registry Number:
    Arsenite (CAS RN 15502-74-6)
  • Federal Fiscal Year:
    2006
  • NORA Priority Area:
    Research Tools and Approaches: Cancer Research Methods
  • Peer Reviewed:
    True
  • Part Number:
    1
  • Source Full Name:
    Biochemical Journal
  • Collection(s):
  • Main Document Checksum:
    urn:sha-512:3d9dd9109aae4d76392c89274de803117885e19287f328f6fdba1c3aa5e93f681d6f59c4c8540e86178f441dd4e48401d1e389c93b9bc8fdecbc1bcb03e1b7f0
  • Download URL:
  • File Type:
    Filetype[PDF - 1.85 MB ]
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