title: Functional interaction of CREB binding protein (CBP) with nuclear transport proteins and modulation by HDAC inhibitors.
abstract: Nuclear transport proteins such as CSE1, NUP93 and Importin-alpha have recently been shown to be chromatin-associated proteins in yeast, which have unexpected functions in gene regulation. Here we report interactions between the mammalian histone acetyltransferase CBP with nuclear transport proteins CAS (a CSE1 homologue) and Importin-alpha (Impalpha) and NUP93. CAS was found to bind the SRC1 interaction domain (SID) of CBP via a leucine-rich motif in the N-terminus of the protein, that is conserved in other SID-binding proteins. Coimmunoprecipitation experiments also revealed that CBP and Impalpha proteins form a complex. As Impalpha is a known acetylation target of CBP/p300, and is recycled to the cytoplasm via the exportin CAS, we investigated whether HDAC inhibitors would alter the subcellular localization of these proteins. Treatment of COS-1 cells with the HDAC inhibitors trichostatin A or sodium butyrate resulted in sequestration of Impalpha in the nuclear envelope, accumulation of CAS in nuclear aggregates, and an increased number of CBP-containing PML bodies per cell. In addition, HDACi treatment appeared to enhance the association of Impalpha and CBP in coimmunoprecipitation experiments. Our results provide evidence for novel functional interactions between the chromatin modification enzyme CBP and nuclear transport proteins in mammalian cells.
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Colm M
authors.initials: CM
authors.lastname: Ryan
authors.forename: Janet C
authors.initials: JC
authors.lastname: Harries
authors.forename: Karin B
authors.initials: KB
authors.lastname: Kindle
authors.forename: Hilary M
authors.initials: HM
authors.lastname: Collins
authors.forename: David M
authors.initials: DM
authors.lastname: Heery
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D020816:Amino Acid Motifs / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019556:COS Cells; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002522:Chlorocebus aethiops; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D009685:Nuclear Envelope / Q000187:drug effects / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism
chemical_list: C493842:Bcar1 protein, mouse; D002352:Carrier Proteins; D050719:Crk-Associated Substrate Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D046911:Macromolecular Substances; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C508154:Nup93 protein, human; D028901:alpha Karyopherins; C087978:karyopherin alpha 2; D050882:CREB-Binding Protein; D006655:Histone Deacetylases