title: Oxidative-stress-induced nuclear to cytoplasmic relocalization is required for Not4-dependent cyclin C destruction.
abstract: The yeast cyclin-C-Cdk8p kinase complex represses the transcription of a subset of genes involved in the stress response. To relieve this repression, cyclin C is destroyed in cells exposed to H(2)O(2) by the 26S proteasome. This report identifies Not4p as the ubiquitin ligase mediating H(2)O(2)-induced cyclin C destruction. Not4p is required for H(2)O(2)-induced cyclin C destruction in vivo and polyubiquitylates cyclin C in vitro by utilizing Lys48, a ubiquitin linkage associated with directing substrates to the 26S proteasome. Before its degradation, cyclin C, but not Cdk8p, translocates from the nucleus to the cytoplasm. This translocation requires both the cell-wall-integrity MAPK module and phospholipase C, and these signaling pathways are also required for cyclin C destruction. In addition, blocking cytoplasmic translocation slows the mRNA induction kinetics of two stress response genes repressed by cyclin C. Finally, a cyclin C derivative restricted to the cytoplasm is still subject to Not4p-dependent destruction, indicating that the degradation signal does not occur in the nucleus. These results identify a stress-induced proteolytic pathway regulating cyclin C that requires nuclear to cytoplasmic relocalization and Not4p-mediated ubiquitylation.
authors.affiliation: Department of Molecular Biology, University of Medicine and Dentistry New Jersey, Two Medical Center Drive, Stratford, NJ 08055,  USA.
authors.forename: Katrina F
authors.initials: KF
authors.lastname: Cooper
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Scarnati
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Krasley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mallory
authors.forename: Chunyan
authors.initials: C
authors.lastname: Jin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Law
authors.forename: Randy
authors.initials: R
authors.lastname: Strich
mesh_terms: D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism; D056745:Cyclin C / Q000378:metabolism*; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056745:Cyclin C; D012331:RNA, Fungal; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; C086923:MOT2 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D056850:Cyclin-Dependent Kinase 8; C498309:SSN3 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae; D010738:Type C Phospholipases