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Inhibitory effects of deferoxamine on UVB-induced AP-1 transactivation
K Kramer-Stickland1, A Edmonds, W B Bair
1Department of Radiation Oncology, The University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Abstract:
Production of reactive oxygen species (ROS) by iron can contribute directly to DNA and protein damage and may contribute to cell signaling and proliferation. We have examined the effects of the iron(III) chelator deferroxamine (DFO) and iron (FeCl(3)) on UVB (290-320 nm)-induced activator protein 1 (AP-1) signaling. The ability of DFO to inhibit UVB-induced AP-1 transactivation was tested in a human keratinocyte cell line stably transfected with a luciferase reporter driven by a single AP-1 element. DFO treatment 24 h prior to UVB irradiation reduced UVB-induced AP-1 transactivation by approximately 80%, with the effect of DFO diminishing as pre-treatment time was shortened. Treatment with FeCl(3) a minimum of 6 h prior to UVB potentiated the UVB induction of AP-1 transactivation by 2-3-fold. DFO was able to ablate both the UVB induction of AP-1 transactivation as well as the potentiation by FeCl(3). The antioxidants Trolox and N-acetyl cysteine were both able to inhibit UVB-induced AP-1 transactivation and Trolox was able to inhibit the potentiation of UVB-induced AP-1 by FeCl(3). These results indicate that UVB-induced AP-1 activation may be in part due to oxidant effects of UVB and intercellular iron.
Insights
Iron and reactive oxygen species (ROS) influence UVB-induced activator protein 1 (AP-1) signaling. The iron chelator deferroxamine (DFO) inhibited AP-1 activation, while iron potentiated it, suggesting a role for iron in skin cell responses to UV radiation.
Area of Science:
- Biochemistry
- Dermatology
- Molecular Biology
Background:
- Reactive oxygen species (ROS) generated by iron contribute to DNA and protein damage.
- ROS also play roles in cell signaling pathways, including proliferation.
- UVB radiation is known to induce cellular stress and signaling cascades.
Purpose of the Study:
- To investigate the role of iron in UVB-induced activator protein 1 (AP-1) signaling.
- To examine the effects of deferroxamine (DFO), an iron chelator, and iron (FeCl3) on AP-1 activation.
- To determine if antioxidants can modulate UVB-induced AP-1 signaling and iron potentiation.
Main Methods:
- Utilized a human keratinocyte cell line engineered with an AP-1 luciferase reporter.
- Assessed AP-1 transactivation following UVB irradiation with varying pre-treatment times of DFO or FeCl3.
- Evaluated the impact of antioxidants (Trolox, N-acetyl cysteine) on AP-1 signaling.
Main Results:
- Deferroxamine (DFO) pre-treatment significantly inhibited UVB-induced AP-1 transactivation by approximately 80%.
- Iron (FeCl3) pre-treatment potentiated UVB-induced AP-1 activation by 2-3 fold.
- DFO effectively blocked both UVB-induced AP-1 activation and iron-mediated potentiation; antioxidants also inhibited these pathways.
Conclusions:
- UVB-induced AP-1 activation is partly mediated by oxidative stress and intracellular iron.
- Iron chelation with DFO can mitigate UVB-induced AP-1 signaling.
- Antioxidants demonstrate potential in counteracting UV-induced cellular signaling pathways involving iron.