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Molecular and Cellular Biology, December 2001, p. 8007-8021, Vol. 21, No. 23
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.8007-8021.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Construction and Analysis of Mouse Strains Lacking the
Ubiquitin Ligase UBR1 (E3
) of the N-End Rule Pathway
Yong Tae
Kwon,1
Zanxian
Xia,1
Ilia V.
Davydov,1,
Stewart H.
Lecker,2 and
Alexander
Varshavsky1,*
Division of Biology, California Institute of
Technology, Pasadena, California 91125,1 and
Renal Unit, Beth Israel Deaconess Medical Center, Boston,
Massachusetts 021152
Received 6 June 2001/Accepted 6 September 2001
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 (E3
). 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 ubr1
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 (E3
). We consider these UBR1-like proteins and
discuss the functions of the mammalian N-end rule pathway.
*
Corresponding author. Mailing address: Division of
Biology, 147-75, Caltech, 1200 East California Blvd., Pasadena, CA
91125. Phone: (626) 395-3785. Fax: (626) 440-9821. E-mail:
avarsh{at}caltech.edu.

Present address: IGEN International, Inc., Gaithersburg, MD
20877.
Molecular and Cellular Biology, December 2001, p. 8007-8021, Vol. 21, No. 23
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.8007-8021.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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