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Complementary DNA Encoding Human Colon Cancer Manganese Superoxide Dismutase and the Expression of Its Gene in Human Cells¹

Experimental Radiation Oncology, Department of Radiology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27103

Manganese superoxide dismutase (MnSOD) is a member of a family of metalloenzymes that catalyze the dismutation of the superoxide anion to H₂O₂. It has been shown that MnSOD activity in tumor cells is lower than that in their normal counterparts. To investigate the molecular basis for the reduced level of MnSOD activity in human tumor cells, the primary structure of human MnSOD has been determined from complementary DNA (cDNA) isolated from a human colon carcinoma (HT-29) cDNA library. The sequence of the mature protein is composed of 198 amino acids preceded by a 24-amino acid leader peptide. DNA sequence analysis revealed that the translated region of the human tumor MnSOD is virtually identical to the MnSOD sequence isolated from normal human sources but exhibits differences in both the 5'- and 3'-untranslated regions. DNA blot analysis of genomic DNA isolated from HT-29, simian virus-transformed human lung fibroblast (SV-40/WI-38), and parental human lung fibroblast (WI-38) cells showed an identical pattern of hybridization to that of MnSOD cDNA. RNA blot analysis revealed that tumor cells have lower levels of MnSOD mRNA. However, the half-life of the mRNA was the same (approximately 10 h) in tumor and normal cells. Immunological measurement of the level of MnSOD in both normal and tumor cells also showed a reduced level of MnSOD protein in the tumor cells. These results suggest that the reduced level of MnSOD activity observed in human tumor cells is not due to a defect in the primary structure of the MnSOD protein, a change in the dosage of the MnSOD gene, or a decrease in the stability of MnSOD mRNA in tumor cells but rather is due to a defect or defects in the expression of the gene.

¹ This work was supported by NIH Grants RR 0504, CA 12197, and CA 49797 and a grant from the Forsyth Cancer Service, Inc.

² To whom requests for reprints should be addressed, at Department of Radiology, Bowman Gray School of Medicine, 300 S. Hawthorne Road, Winston-Salem, NC 27103.

Received 6/ 4/90. Accepted 11/ 9/90.

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