PMID:11689692

Citation	Kwon, YT, Xia, Z, Davydov, IV, Lecker, SH and Varshavsky, A (2001) Construction and analysis of mouse strains lacking the ubiquitin ligase UBR1 (E3alpha) of the N-end rule pathway. Mol. Cell. Biol. 21:8007-21
Abstract	The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. In the yeast Saccharomyces cerevisiae, the UBR1-encoded ubiquitin ligase (E3) of the N-end rule pathway mediates the targeting of substrate proteins in part through binding to their destabilizing N-terminal residues. The functions of the yeast N-end rule pathway include fidelity of chromosome segregation and the regulation of peptide import. Our previous work described the cloning of cDNA and a gene encoding the 200-kDa mouse UBR1 (E3alpha). Here we show that mouse UBR1, in the presence of a cognate mouse ubiquitin-conjugating (E2) enzyme, can rescue the N-end rule pathway in ubr1Delta S. cerevisiae. We also constructed UBR1(-/-) mouse strains that lacked the UBR1 protein. UBR1(-/-) mice were viable and fertile but weighed significantly less than congenic +/+ mice. The decreased mass of UBR1(-/-) mice stemmed at least in part from smaller amounts of the skeletal muscle and adipose tissues. The skeletal muscle of UBR1(-/-) mice apparently lacked the N-end rule pathway and exhibited abnormal regulation of fatty acid synthase upon starvation. By contrast, and despite the absence of the UBR1 protein, UBR1(-/-) fibroblasts contained the N-end rule pathway. Thus, UBR1(-/-) mice are mosaics in regard to the activity of this pathway, owing to differential expression of proteins that can substitute for the ubiquitin ligase UBR1 (E3alpha). We consider these UBR1-like proteins and discuss the functions of the mammalian N-end rule pathway.
Links	PubMed PMC99968 Online version:10.1128/MCB.21.23.8007-8021.2001
Keywords	Adipose Tissue/chemistry; Adipose Tissue/metabolism; Amidohydrolases/deficiency; Amidohydrolases/genetics; Amidohydrolases/metabolism; Animals; Body Weight/genetics; Cells, Cultured; Crosses, Genetic; Fatty Acids/biosynthesis; Fibroblasts/metabolism; Ligases/metabolism; Mice; Mice, Inbred Strains; Mice, Knockout; Muscle, Skeletal/chemistry; Muscle, Skeletal/metabolism; Phenotype; Proteins/genetics; Proteins/metabolism; RNA, Messenger/biosynthesis; Saccharomyces cerevisiae/metabolism; Signal Transduction/physiology; Starvation/metabolism; Transfection; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases
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