title: Activation of AP-1-dependent transcription by a truncated translation initiation factor.
abstract: Int6/eIF3e is a highly conserved subunit of eukaryotic translation initiation factor 3 (eIF3) that has also been reported to interact with subunits of the proteasome and the COP9 signalosome. Overexpression of full-length Int6 or a 13-kDa C-terminal fragment, Int6CT, in the fission yeast Schizosaccharomyces pombe causes multidrug resistance that requires the otherwise inessential AP-1 transcription factor Pap1. Here we show for the first time that Int6CT acts to increase the transcriptional activity of Pap1. Microarray hybridization data indicate that Int6CT overexpression resulted in the up-regulation of 67 genes; this expression profile closely matched that of cells overexpressing Pap1. Analysis of the upstream regulatory sequences of these genes showed that the majority contained AP-1 consensus binding sites. Partial defects in ubiquitin-dependent proteolysis have been suggested to confer Pap1-dependent multidrug resistance, but no such defect was seen on Int6CT overexpression. Indeed, none of the previously identified interactions of endogenous Int6 was required for the activation of Pap1 transcription described here. Moreover, Int6CT-induced activation of Pap1-responsive gene expression was independent of the ability of Pap1 to undergo a redox-regulated conformational change which mediates its relocalization to the nucleus and expression of oxidative stress response genes. Int6CT therefore activates Pap1-dependent transcription by a novel mechanism.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Caroline C L
authors.initials: CC
authors.lastname: Jenkins
authors.forename: Juan
authors.initials: J
authors.lastname: Mata
authors.forename: Richard F
authors.initials: RF
authors.lastname: Crane
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thomas
authors.forename: Alexandre
authors.initials: A
authors.lastname: Akoulitchev
authors.forename: Jürg
authors.initials: J
authors.lastname: Bähler
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Norbury
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D004352:Drug Resistance, Microbial / Q000235:genetics*; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D017930:Genes, Reporter; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D000073718:Pancreatitis-Associated Proteins; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011487:Protein Conformation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013831:Thiamine / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D039621:Eukaryotic Initiation Factor-3; D046912:Multiprotein Complexes; D000073718:Pancreatitis-Associated Proteins; C105096:Pap1 protein, S pombe; D021122:Protein Subunits; C000612141:REG3A protein, human; D011993:Recombinant Fusion Proteins; D029702:Schizosaccharomyces pombe Proteins; D018808:Transcription Factor AP-1; D025821:Polyubiquitin; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D018631:ras Proteins; D013831:Thiamine