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1070343 
Journal Article 
Effects of arsenite and UVA-1 radiation on calcineurin signaling 
Musson, REA; Mullenders, LHF; Smit, NPM 
In Press 
Yes 
Mutation Research
ISSN: 0027-5107
EISSN: 1873-135X 
735 
1-2 
32-38 
English 
Calcineurin is a Ca(2+)-dependent serine/threonine phosphatase and the target of the immunosuppressive drugs cyclosporin and tacrolimus, which are used in transplant recipients to prevent rejection. Unfortunately, the therapeutic use of this drugs is complicated by a high incidence of skin malignancy, which has set off a number of studies into the role of calcineurin signaling in skin, particularly with respect to cell cycle control and DNA repair. Both UVA1 radiation and arsenic species are known to promote skin cancer development via production of reactive oxygen species. In light of the well-documented sensitivity of calcineurin to oxidative stress, we examined and compared the effects of UVA1 and arsenite on calcineurin signaling. In this paper, we show that physiologically relevant doses of UVA1 radiation and low micromolar concentrations of arsenite strongly inhibit calcineurin phosphatase activity in Jurkat and skin cells and decrease NFAT nuclear translocation in Jurkat cells. The effects on calcineurin signaling could be partly prevented by inhibition of NADPH oxidase in Jurkat cells or increased dismutation of superoxide in Jurkat and skin cells. In addition, both UVA1 and arsenite decreased NF-κB activity, although at lower concentrations, arsenite enhanced NF-κB activity. These data indicate that UVA1 and arsenite affect a signal transduction route of growingly acknowledged importance in skin and that calcineurin may serve as a potential link between ROS exposure and impaired tumor suppression. 
Calcineurin; Reactive oxygen species; UVA radiation; Arsenite; NFAT; Skin carcinogenesis 
IRIS
• Arsenic Hazard ID
     1. Initial Lit Search
          PubMed
          WOS
          WOS
          Excluded
               Non Peer Reviewed
     2. Lit Search Updates through Oct 2015
          WOS
          Initial Filter
               Non Peer Reviewed
     3. Initial Filter through Oct 2015
          Non Peer-Reviewed
     7. Other Studies through Oct 2015
          MOA
• Arsenic (Inorganic)
     1. Literature
          PubMed
          Web of Science
          Lit search updates through Oct 2015
     2. Initial Filter
          Non peer-reviewed
     3. Hazard ID Screening
          Other potentially supporting studies
     4. Adverse Outcome Pathways/Networks Screening
          Relevant
• Arsenic MOA
     4. Adverse Outcome Pathways
          Other MOA
     5. Health Effect
          Skin Diseases
          Cancer
     1. MOA Literature Screening
          Health Effect Screening
• Arsenic Susceptibility
     Life Stages Citation Mapping
          20%-25%