title: Oxidative stress-induced destruction of the yeast C-type cyclin Ume3p requires phosphatidylinositol-specific phospholipase C and the 26S proteasome.
abstract: The yeast UME3 (SRB11/SSN3) gene encodes a C-type cyclin that represses the transcription of the HSP70 family member SSA1. To relieve this repression, Ume3p is rapidly destroyed in cells exposed to elevated temperatures. This report demonstrates that Ume3p levels are also reduced in cultures subjected to ethanol shock, oxidative stress, or carbon starvation or during growth on nonfermentable carbons. Of the three elements (RXXL, PEST, and cyclin box) previously shown to be required for heat-induced Ume3p destruction, only the cyclin box regulates Ume3p degradation in response to these stressors. The one exception observed was growth on nonfermentable carbons, which requires the PEST region. These findings indicate that yeast cells contain multiple, independent pathways that mediate stress-induced Ume3p degradation. Ume3p destruction in response to oxidative stress, but not to ethanol treatment, requires DOA4 and UMP1, two factors required for 26S proteasome activity. This result for the first time implicates ubiquitin-mediated proteolysis in C-type cyclin regulation. Similarly, the presence of a membrane stabilizer (sorbitol) or the loss of phosphatidylinositol-specific phospholipase C (PLC1) protects Ume3p from oxidative-stress-induced degradation. Finally, a ume3 null allele suppresses the growth defect of plc1 mutants in response to either elevated temperature or the presence of hydrogen peroxide. These results indicate that the growth defects observed in plc1 mutants are due to the failure to downregulate Ume3p. Taken together, these findings support a model in which Plc1p mediates an oxidative-stress signal from the plasma membrane that triggers Ume3p destruction through a Doa4p-dependent mechanism.
authors: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors: K F
authors: KF
authors: Cooper
authors: M J
authors: MJ
authors: Mallory
authors: R
authors: R
authors: Strich
mesh_terms: D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism*; D010450:Endopeptidases; D056827:Endosomal Sorting Complexes Required for Transport; D000431:Ethanol / Q000494:pharmacology; D005656:Fungal Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006358:Hot Temperature; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000378:metabolism*; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013012:Sorbitol / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D016213:Cyclins; C084434:DOA4 protein, S cerevisiae; D056827:Endosomal Sorting Complexes Required for Transport; D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D014452:Ubiquitins; C110856:proteasome maturation protein; D000431:Ethanol; D013012:Sorbitol; D006861:Hydrogen Peroxide; C093345:SSN8 protein, S cerevisiae; D018844:Cyclin-Dependent Kinases; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D010450:Endopeptidases; D010447:Peptide Hydrolases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D043265:Phosphatidylinositol Diacylglycerol-Lyase