Ubiquitin-proteasome-mediated CREB repressor degradation during induction of long-term facilitation.
Abstract Long-term facilitation in Aplysia and other forms of long-term memory in invertebrates and vertebrates require the gene expression cascade induced by cAMP-responsive element binding protein (CREB). Normally, gene expression by CREB is inhibited by repressors. The molecular mechanisms by which the repression is relieved are not understood. Our results show that Aplysia CREB repressor is a substrate for degradation by the ubiquitin-proteasome pathway. Treatment with the facilitatory neurotransmitter 5-hydroxy tryptamine (5-HT) leads to CREB repressor degradation in vivo and the degradation can be blocked by a specific proteasome inhibitor. Our biochemical studies show that attachment of ubiquitin molecules marks the CREB repressor for degradation by the proteasome. Protein kinase C (PKC) stimulates ubiquitination and degradation of the CREB repressor. Our results suggest that proteolytic removal of the CREB repressor is a potential mechanism for controlling gene expression by CREB. Without stimulation, gene expression is suppressed by the CREB repressor. Upon stimulation with 5-HT, PKC is activated, causing enhancement in ubiquitination and degradation of the CREB repressor. Thus, regulation of proteolysis of the CREB repressor by PKC might be critical in determining whether or not CREB-mediated gene expression goes forward during induction of long-term facilitation.
Upadhya
Sudarshan C
SC
Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
Smith
Thuy K
TK
Hegde
Ashok N
AN
D000818:Animals; D001048:Aplysia; D002118:Calcium / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism*; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D015151:Immunoblotting / Q000379:methods; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007783:Lactones; D012097:Repressor Proteins; D025801:Ubiquitin; D012701:Serotonin; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D002118:Calcium