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The rat Cu/Zn superoxide dismutase (SOD1) is expressed in all tissues. Sequence analysis of the SOD1 promoter region showed that none of the cis-elements of hepatocyte-specific nuclear factors (HNF) were observed. The cis-element of C/EBPα in the proximal region of the SOD1 promoter and the high level of C/EBPα in the liver tissue led us to focus on the transcriptional regulation of the SOD1 gene by C/EBPα. Cotransfection assays with the plasmid expressing transcription factor C/EBPα showed that C/EBPα transactivated SOD1 gene by 27 fold. The marked transactivation and direct binding of C/EBPα to the SOD1 promoter were confirmed by deletion analyses and mobility shift assays. These results suggested that C/EBPα plays a major role in the tissue distribution of SOD1.