Superoxide dismutase as an inhibitor of erythroid progenitor cell cycling.
C57Bl/6 (B6) mice and mice of a congeneic strain, B6S, differ in the proportions of erythroid progenitor cells (BFU-E) typically seen in DNA synthesis in in vivo cell suicide assays, and bone marrow supernatants (MS) prepared from B6 mice can inhibit BFU-E cycling in vitro. Using in vitro BFU-E DNA synthesis assays and a model system of BFU-E in culture (DA-1 cells) as screening methods for the detection of inhibitors of BFU-E cycling, we have purified the protein that is apparently responsible for the inhibitory effects of MS on progenitor cells and that is also an antagonist of the stimulatory effects of interleukin-3 (IL-3) on DA-1 cell proliferation in culture. We have identified this protein as the Cu,Zn-containing form of the antioxidant enzyme superoxide dismutase (SOD), which is normally present in large amounts in erythrocytes. MS from B6S mice does not inhibit BFU-E DNA synthesis. However, measurements of SOD activity showed no differences between B6 and B6S mice; thus the difference between the effects of B6S-MS and B6-MS is not due to differences in the levels of SOD present. The inhibitory effects of SOD on BFU-E in vitro are opposed by the stimulatory effects of IL-3 in a dose-dependent manner, and similar interactions between stimulatory and inhibitory factors also appear to determine the effects of mouse-derived preparations on erythroid cells. If the interactions seen in vitro are applicable to the state in vivo, SOD may be a constitutive inhibitor of erythroid progenitor cell cycling in mice, acting in opposition to stimulatory factors whose expression varies in response to genetic and physiological influences.
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Department of Anatomy, University of Toronto, Ontario, Canada.
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D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004920:Erythropoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013482:Superoxide Dismutase / Q000494:pharmacology / Q000502:physiology*
D007377:Interleukin-3; D013482:Superoxide Dismutase