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Independent Regulation of Ornithine Decarboxylase and S-Adenosylmethionine Decarboxylase in Methylthioadenosine Phosphorylase-deficient Malignant Murine Lymphoblasts¹

Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037

The control of polyamine synthesis in neoplastic cells is complex and incompletely understood. Using murine lymphoma cells deficient in methylthioadenosine (MTA) phosphorylase, we have analyzed the role of MTA in the regulation of ornithine decarboxylase and S-adenosylmethionine (SAM) decarboxylase, the two rate-limiting enzymes in the polyamine-biosynthetic pathway. The addition of MTA to the enzyme-deficient lymphoblasts induced within 1 to 3 h an increase in the activities of both decarboxylases and an accompanying rise in putrescine and decarboxylated SAM levels. The ornithine decarboxylase inhibitor -difluoromethylornithine blocked the MTA-triggered accumulation of putrescine but not decarboxylated SAM. In a reciprocal manner, the SAM decarboxylase inhibitor methylglyoxal bis(guanylhydrazone) prevented the accretion of decarboxylated SAM but not putrescine. The MTA-induced rise in SAM decarboxylase and ornithine decarboxylase activities preceded by several hours changes in spermidine or spermine pools. However, MTA decreased the flux through the polyamine-synthetic pathway, as estimated by the incorporation of radioactive ornithine into spermine. Similar changes in polyamine metabolism were observed in a secondary mutant deficient in MTA phosphorylase, but resistant to MTA toxicity. These results suggest that the velocity of polyamine synthesis, or the concentration of MTA itself, may regulate ornithine decarboxylase and SAM decarboxylase activities through separate, growth-independent mechanisms.

¹ This work is supported by Grants CA31497 and CA35048 from the National Cancer Institute, and by Grant GM23200 from the NIH. This is Publication 3750BCR from the Research Institute of Scripps Clinic, La Jolla, CA 92037.

² To whom requests for reprints should be addressed, at Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037.

Received 1/30/85. Revised 4/25/85. Accepted 5/ 1/85.

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