A coding region determinant of instability regulates levels of manganese superoxide dismutase mRNA.

The mitochondria-localized manganese superoxide dismutase (MnSOD), serves a key cytoprotective role against reactive oxygen species arising from a variety of cellular processes and immunological stresses. Previous data from our laboratory suggest that the regulation of the rat MnSOD gene may occur not only at the transcriptional but quite possibly at the post-transcriptional level. To verify this hypothesis, we have attempted to identify regions within the rat MnSOD cDNA that may be functionally involved in regulating the stability of the mRNA. Using a c-fos-based promoter activation system, we have identified an approximately 280-nucleotide fragment within the MnSOD mRNA coding region that, when fused to a rabbit beta-globin gene, destabilizes the normally stable beta-globin mRNA. This cis-directed destabilization phenomenon confers its effects independent of position and stimulus. Most importantly, the MnSOD coding region determinant functions when placed in the 3'-untranslated region of the beta-globin transcript, demonstrating its activity in the absence of ribosome transit. We feel that these data provide a mechanistic basis for both the basal and stimulus-dependent post-transcriptional regulation of MnSOD.