title: Ubiquitin-dependent distribution of the transcriptional coactivator p300 in cytoplasmic inclusion bodies.
abstract: The protein level of transcriptional coactivator p300, an essential nuclear protein, is critical to a broad array of cellular activities including embryonic development, cell differentiation and proliferation. We have previously established that histone deacetylase inhibitor such as valproic acid induces p300 degradation through the 26S proteasome pathway. Here, we report the roles of cellular trafficking and spatial redistribution in valproic acid-induced p300 turnover. Our study demonstrates that p300 is redistributed to the cytoplasm prior to valproic acid-induced turnover. Inhibition of proteasome-dependent protein degradation, does not prevent nucleo-cytoplasmic shuttling of p300, rather sequesters the cytoplasmic p300 to a distinct perinuclear region. In addition, the formation of p300 aggregates in the perinuclear region depends on functional microtubule networks and correlates with p300 ubiquitination. Our work establishes, for the first time, that p300 is also a substrate of the cytoplasmic ubiquitin-proteasome system and provides insight on how cellular trafficking and spatial redistribution regulate the availability and activity of transcriptional coactivator p300.
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jihong
authors.initials: J
authors.lastname: Chen
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
authors.forename: John P H
authors.initials: JP
authors.lastname: Th' ng
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
mesh_terms: D002087:Butyrates / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D007700:Kinetics; D007976:Leupeptins / Q000494:pharmacology; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D002087:Butyrates; D007976:Leupeptins; D025801:Ubiquitin; D014635:Valproic Acid; D050880:p300-CBP Transcription Factors; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde