title: Metabolic control of G1-S transition: cyclin E degradation by p53-induced activation of the ubiquitin-proteasome system.
abstract: Cell cycle progression is precisely regulated by diverse extrinsic and intrinsic cellular factors. Previous genetic analysis in Drosophila melanogaster has shown that disruption of the mitochondrial electron transport chain activates a G1-S checkpoint as a result of a control of cyclin E by p53. This regulation does not involve activation of the p27 homologue dacapo in flies. We demonstrate that regulation of cyclin E is not at the level of transcription or translation. Rather, attenuated mitochondrial activity leads to transcriptional upregulation of the F-box protein archipelago, the Fbxw7 homologue in flies. We establish that archipelago and the proteasomal machinery contribute to degradation of cyclin E in response to mitochondrial dysfunction. Our work provides in vivo genetic evidence for p53-mediated integration of metabolic stress signals, which modulate the activity of the ubiquitin-proteasome system to degrade cyclin E protein and thereby impose cell cycle arrest.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sudip
authors.initials: S
authors.lastname: Mandal
authors.forename: William A
authors.initials: WA
authors.lastname: Freije
authors.forename: Preeta
authors.initials: P
authors.lastname: Guptan
authors.forename: Utpal
authors.initials: U
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D001483:Base Sequence; D019927:Cyclin E / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D003576:Electron Transport Complex IV / Q000235:genetics; D004789:Enzyme Activation; D005123:Eye / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D016193:G1 Phase; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D019927:Cyclin E; D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D003576:Electron Transport Complex IV; D046988:Proteasome Endopeptidase Complex