Regulation of the neuronal proteasome by Zif268 (Egr1).
Most forms of neuronal plasticity are associated with induction of the transcription factor Zif268 (Egr1/Krox24/NGF-IA). In a genome-wide scan, we obtained evidence for potential modulation of proteasome subunit and regulatory genes by Zif268 in neurons, a finding of significance considering emerging evidence that the proteasome modulates synaptic function. Bioinformatic analysis indicated that the candidate proteasome Zif268 target genes had a rich concentration of putative Zif268 binding sites immediately upstream of the transcriptional start sites. Regulation of the mRNAs encoding the psmb9 (Lmp2) and psme2 (PA28beta) proteasome subunits, along with the proteasome-regulatory kinase serum/glucocorticoid-regulated kinase (SGK) and the proteasome-associated antigen peptide transporter subunit 1 (Tap1), was confirmed after transfection of a neuronal cell line with Zif268. Conversely, these mRNAs were upregulated in cerebral cortex tissue from Zif268 knock-out mice relative to controls, confirming that Zif268 suppresses their expression in the CNS. Transfected Zif268 reduced the activity of psmb9, SGK, and Tap1 promoter-reporter constructs. Altered psmb9, SGK, and Tap1 mRNA levels were also observed in an in vivo model of neuronal plasticity involving Zif268 induction: the effect of haloperidol administration on striatal gene expression. Consistent with these effects on proteasome gene expression, increased Zif268 expression suppressed proteasome activity, whereas Zif268 knock-out mice exhibited elevated cortical proteasome activity. Our findings reveal that Zif268 regulates the expression of proteasome and related genes in neuronal cells and provide new evidence that altered expression of proteasome activity after Zif268 induction may be a key component of long-lasting CNS plasticity.
James
Allan B
AB
Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom. A.James@bio.gla.ac.uk
Conway
Ann-Marie
AM
Morris
Brian J
BJ
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology / Q000502:physiology; D019295:Computational Biology; D003546:Cysteine Endopeptidases / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D017874:Immediate-Early Proteins / Q000235:genetics; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology* / Q000502:physiology; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation; D000099184:Serum-Glucocorticoid Regulated Kinases
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D003546:Cysteine Endopeptidases; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D000099184:Serum-Glucocorticoid Regulated Kinases; C486109:Egr1 protein, mouse; C486172:Tap1 protein, rat; C071313:LMP-2 protein