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Most forms of neuronal plasticity are associated with induction of the transcription factor zif268 (egr1). Down-regulation of cdc20 (p55cdc)—a regulatory protein for the anaphase-promoting complex, which controls access of specific substrates to the proteasome—was observed after transfection of a neuronal cell line with zif268. Treatment of cultured hippocampal neurones with NMDA, which elevates endogenous zif268 levels, also decreased cdc20 levels. Conversely, the levels of cdc20 were found to be increased in the cerebral cortex of mice with targeted deletion of the zif268 gene, when compared with wild-type controls. Our findings indicate that expression of the cdc20 gene is down-regulated by zif268 in neuronal cells, and provide new evidence that altered expression of proteasome-regulatory genes following zif268 induction may be a key component of long-lasting CNS plasticity.