Regulation of reactive oxygen species homeostasis by peroxiredoxins and c-Myc.
Peroxiredoxins (Prxs) are highly conserved proteins found in most organisms, where they function primarily to scavenge reactive oxygen species (ROS). Loss of the most ubiquitous member of the family, Prx1, is associated with the accumulation of oxidatively damaged DNA and a tumor-prone phenotype. Prx1 interacts with the transcriptional regulatory domain of the c-Myc oncoprotein and suppresses its transforming activity. The DNA damage in tissues of prx1-/- mice is associated in some cases with only modest increases in total ROS levels. However, these cells show dramatic increases in nuclear ROS and reduced levels of cytoplasmic ROS, which explains their mutational susceptibility. In the current work, we have investigated whether changes in other ROS scavengers might account for the observed ROS redistribution pattern in prx1-/- cells. We show approximately 5-fold increases in Prx5 levels in prx1-/- embryo fibroblasts relative to prx1+/+ cells. Moreover, Prx5 levels normalize when Prx1 expression is restored. Prx5 levels also appear to be highly dependent on c-Myc, and chromatin immunoprecipitation experiments showed differential occupancy of c-Myc and Prx1 complexes at E-box elements in the prx5 gene proximal promoter. This study represents a heretofore unreported mechanism for the c-Myc-dependent regulation of one Prx family member by another and identifies a novel means by which cells reestablish ROS homeostasis when one of these family members is compromised.
Graves
J Anthony
JA
Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital of Pittsburgh, and University of Pittsburgh Medical Center, Department of Microbiology and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Metukuri
Mallikarjuna
M
Scott
Donald
D
Rothermund
Kristi
K
Prochownik
Edward V
EV
D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics; D004249:DNA Damage / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D054464:Peroxiredoxins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; C515975:Prdx5 protein, mouse