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Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1
Rachel A Egler1, Elaine Fernandes, Kristi Rothermund
1Department of Pediatrics, Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Rangos Research Center, 3460 Fifth Ave., USA.
Abstract:
Overexpression of c-Myc results in transformation and multiple other phenotypes, and is accompanied by the deregulation of a large number of target genes. We previously demonstrated that peroxiredoxin 1 (Prdx1), a scavenger of reactive oxygen species (ROS), interacts with a region of the c-Myc transcriptional regulatory domain that is essential for transformation. This results either in the suppression or enhancement of some c-Myc functions and in the altered expression of select target genes. Most notably, c-Myc-mediated transformation is inhibited, implying a tumor suppressor role for Prdx1. Consistent with this, prdx1-/- mice develop age-dependent hemolytic anemias and/or malignancies. We now show that erythrocytes and embryonic fibroblasts from these animals contain higher levels of ROS, and that the latter cells show evidence of c-Myc activation, including the ability to be transformed by a ras oncogene alone. In contrast, other primary cells from prdx1-/- mice do not have elevated ROS, but nonetheless show increased oxidative DNA damage. This apparent paradox can be explained by the fact that ROS localize primarily to the cytoplasm of prdx1+/+ cells, whereas in prdx1-/- cells, much higher levels of nuclear ROS are seen. We suggest that increased DNA damage and tumor susceptibility in prdx1-/- animals results from this shift in intracellular ROS. prdx1-/- mice should be useful in studying the role of oxidative DNA damage in the causation of cancer and its prevention by antioxidants. They should also help in studying the relationship between oncogenes such as c-Myc and DNA damage.
Insights
Peroxiredoxin 1 (Prdx1) suppresses c-Myc-driven cancer. Mice lacking Prdx1 show increased reactive oxygen species (ROS) in the nucleus, leading to DNA damage and tumor susceptibility.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- c-Myc oncogene overexpression drives cellular transformation and gene deregulation.
- Peroxiredoxin 1 (Prdx1) scavenges reactive oxygen species (ROS) and interacts with c-Myc's regulatory domain.
- Prdx1's interaction with c-Myc modulates its functions, potentially inhibiting transformation.
Purpose of the Study:
- To investigate the role of Prdx1 in c-Myc-mediated transformation and cancer development.
- To analyze the impact of Prdx1 deficiency on cellular ROS levels and DNA damage.
- To elucidate the relationship between Prdx1, ROS localization, and oncogene-induced tumorigenesis.
Main Methods:
- Analysis of prdx1-/- mice for age-dependent phenotypes like anemia and malignancies.
- Measurement of ROS levels in erythrocytes and embryonic fibroblasts from prdx1-/- mice.
- Assessment of c-Myc activation and ras oncogene transformation in prdx1-/- cells.
- Investigation of intracellular ROS localization (cytoplasmic vs. nuclear).
Main Results:
- prdx1-/- mice exhibit hemolytic anemias and/or malignancies.
- Erythrocytes and embryonic fibroblasts from prdx1-/- mice show elevated ROS.
- prdx1-/- embryonic fibroblasts display c-Myc activation and are transformable by ras.
- Nuclear ROS levels are significantly higher in prdx1-/- cells, correlating with increased oxidative DNA damage.
Conclusions:
- Prdx1 acts as a tumor suppressor by mitigating c-Myc-driven transformation.
- Altered intracellular ROS localization, specifically increased nuclear ROS in Prdx1-deficient cells, contributes to DNA damage and cancer susceptibility.
- prdx1-/- mice are valuable models for studying oxidative DNA damage in cancer etiology and the interplay between oncogenes and DNA damage.
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