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Cdc123 and checkpoint forkhead associated with RING proteins control the cell cycle by controlling eIF2gamma abundance
Journal article   Open access   Peer reviewed

Cdc123 and checkpoint forkhead associated with RING proteins control the cell cycle by controlling eIF2gamma abundance

Pawel Bieganowski, Kara Shilinski, Philip N Tsichlis and Charles Brenner
The Journal of biological chemistry, Vol.279(43), pp.44656-44666
10/22/2004
DOI: 10.1074/jbc.M406151200
PMID: 15319434
url
https://doi.org/10.1074/jbc.M406151200View
Published (Version of record) Open Access

Abstract

Eukaryotic initiation factor 2 (eIF2) is a central regulator of translational initiation in times of growth and times of stress. Here we discovered three new conserved regulators of eIF2 in Saccharomyces cerevisiae. cdc123, homolog of mammalian D123, is a new cell division cycle mutant with a G2 delay at permissive temperature and a terminal, mating-proficient G1 arrest point. Cdc123 protein is regulated by nutrient availability. CHF1 and CHF2, homologs of mammalian checkpoint forkhead associated with RING genes, are required for G2 delay and G1 arrest of cdc123-4 and promote G1 delay when over-expressed. Cell cycle delaying activity and the natural instability of Chf1 and Chf2 depend on the integrity of both domains and association with Cdc123. Genetic analysis maps the Chf1 forkhead associated domain-binding site to the conserved Thr-274 of Cdc123, suggesting that mammalian D123 is a key target of Chfr. Gcd11, the gamma subunit of eIF2, is an additional Cdc123-interacting protein that is an essential target of the Cdc123 cell cycle promoting and Chf cell cycle arresting activity whose abundance is regulated by Cdc123, Chf1, and Chf2. Loss of cdc123 activity promotes Chf1 and Chf2 accumulation and Gcd11 depletion, accounting for the essentiality of Cdc123. The data establish the Cdc123-Chf-Gcd11 axis as an essential pathway for nutritional control of START that runs parallel to the Tor-Gcn2-Sui2 system of translational control.
 Immunoprecipitation Flow Cytometry Phenotype Cell Cycle Mutation Eukaryotic Initiation Factor-2 - biosynthesis Protein Biosynthesis Temperature Threonine - chemistry Cell Proliferation Humans Open Reading Frames Molecular Sequence Data Saccharomyces cerevisiae Proteins - biosynthesis Saccharomyces cerevisiae - metabolism Time Factors Base Sequence Gene Deletion beta-Galactosidase - metabolism Cell Cycle Proteins - genetics G2 Phase Binding Sites Protein Structure, Tertiary Amino Acid Sequence Mutagenesis, Site-Directed Gene Expression Regulation Saccharomyces cerevisiae Proteins - genetics Plasmids - metabolism Blotting, Western Sequence Homology, Amino Acid Two-Hybrid System Techniques G1 Phase Models, Biological Eukaryotic Initiation Factor-2 - genetics Alleles Heterozygote Saccharomyces cerevisiae Proteins - physiology Cell Cycle Proteins - physiology

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