title: PSMC5, a 19S Proteasomal ATPase, Regulates Cocaine Action in the Nucleus Accumbens.
abstract: ΔFosB is a stable transcription factor which accumulates in the nucleus accumbens (NAc), a key part of the brain's reward circuitry, in response to chronic exposure to cocaine or other drugs of abuse. While ΔFosB is known to heterodimerize with a Jun family member to form an active transcription factor complex, there has not to date been an open-ended exploration of other possible binding partners for ΔFosB in the brain. Here, by use of yeast two-hybrid assays, we identify PSMC5-also known as SUG1, an ATPase-containing subunit of the 19S proteasomal complex-as a novel interacting protein with ΔFosB. We verify such interactions between endogenous ΔFosB and PSMC5 in the NAc and demonstrate that both proteins also form complexes with other chromatin regulatory proteins associated with gene activation. We go on to show that chronic cocaine increases nuclear, but not cytoplasmic, levels of PSMC5 in the NAc and that overexpression of PSMC5 in this brain region promotes the locomotor responses to cocaine. Together, these findings describe a novel mechanism that contributes to the actions of ΔFosB and, for the first time, implicates PSMC5 in cocaine-induced molecular and behavioral plasticity.
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoko H
authors.initials: YH
authors.lastname: Ohnishi
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Yoshinori N
authors.initials: YN
authors.lastname: Ohnishi
authors.affiliation: The Research Support Center, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kennedy
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohkawa
authors.affiliation: Department of Advanced Medical Initiatives, Division of Epigenetics, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Ohkawa
authors.initials: O
authors.lastname: Yasuyuki
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004265:DNA Helicases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism* / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D003042:Cocaine; D004265:DNA Helicases; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D046988:Proteasome Endopeptidase Complex; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C483819:Fosb protein, mouse; C498709:Pag1 protein, mouse; C491455:Psmc5 protein, mouse; C513194:Smarca4 protein, mouse