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Proteasomal Proteolysis in the Adrenergic Induction of Arylalkylamine-N-Acetyltransferase in Rat Pinealocytes

Departments of Physiology (D.L.T. , D.M.P., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

Address all correspondence and requests for reprints to: Dr. C. L. Chik, Department of Medicine, 7-33 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7. E-mail: cchik{at}ualberta.ca.

In this study, we investigated the effect of proteasomal inhibition on the induction of arylalkylamine-N-acetyltransferase (AA-NAT) enzyme in cultured rat pinealocytes, using two proteasome inhibitors, MG132 and clastolactacystin ß-lactone (c-lact). Addition of c-lact or MG132 3 h after norepinephrine (NE) stimulation produced a significant increase in AA-NAT protein level and enzyme activity. However, when the proteasome inhibitors were added before or together with NE, significant reductions of the NE-induced aa-nat mRNA, protein, and enzyme activity were observed. A similar inhibitory effect of MG132 on aa-nat transcription was observed when cells were stimulated by dibutyryl cAMP, indicating an effect distal to a post-cAMP step. The inhibitory effect of MG132 on adrenergic-induced aa-nat transcription was long lasting because it remained effective after 14 h of washout and appeared specific for aa-nat because the induction of another adrenergic-regulated gene, MAPK phosphatase-1, by NE was not affected. Time-profile studies revealed that the inhibitory effect of MG132 on NE-stimulated aa-nat induction was detected after 1 h, suggesting accumulation of a protein repressor as a possible mechanism of action. This possibility was also supported by the finding that the inhibitory effect of c-lact on NE-induced aa-nat induction was markedly reduced by cycloheximide, a protein synthesis inhibitor. Together, these results support an important role of proteasomal proteolysis in the adrenergic-mediated induction of aa-nat transcription through its effect on a protein repressor.

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