Antizyme protects against abnormal accumulation and toxicity of polyamines in ornithine decarboxylase-overproducing cells.

Exposure of ornithine decarboxylase (ODC; L-ornithine carboxy-lyase, EC 4.1.1.17)-overproducing mouse FM3A cells to micromolar levels of spermine or spermidine caused abnormal accumulation and toxicity of polyamines. This was apparently due to the inefficiency of negative feedback control of polyamine transport by polyamines in ODC-overproducing cells. Since antizyme is the only protein thus far recognized that can interact with ODC, depletion of free antizyme was regarded as the reason for the abnormal accumulation of polyamines. Accordingly, ODC-overproducing cells were transfected with pMAMneoZ1 possessing rat antizyme cDNA under the control of a glucocorticoid-inducible promoter. In the transfected cells, the addition of dexamethasone caused an increase in the amount of antizyme with an apparent molecular mass of 27 kDa, a decrease in the amount of ODC, a decrease in the polyamine transport activity, and the recovery of growth inhibition or cell death. The results indicate that antizyme can regulate not only the amount of ODC but also the activity of polyamine transport.