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Abstract
*Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261; and Division of Biology, California Institute of Technology, Pasadena, CA 91125
Contributed by Alexander Varshavsky, March 2, 2006
The N-endrule relates the in vivo half-life of a protein to the identityof its N-terminal residue. A subset of degradation signals recognizedby the N-end rule pathway comprises the signals, called N-degrons,whose determinants include destabilizing N-terminal residues.Our previous work identified a family of at least four mammalianE3 ubiquitin ligases, including UBR1 and UBR2, that share theUBR box and recognize N-degrons. These E3 enzymes mediate themultifunctional N-end rule pathway, but their individual rolesare just beginning to emerge. Mutations of UBR1 in humans arethe cause of Johanson-Blizzard syndrome. UBR1 and UBR2 are 46%identical and appear to be indistinguishable in their recognitionof N-degrons. UBR1-/- mice are viable but have defects thatinclude pancreatic insufficiency, similarly to UBR1-/- humanpatients with Johanson-Blizzard syndrome. UBR2-/- mice are inviablein some strain backgrounds and are defective in male meiosis.To examine functional relationships between UBR1 and UBR2, weconstructed mouse strains lacking both of these E3s. We reporthere that UBR1-/-UBR2-/- embryos die at midgestation, with defectsin neurogenesis and cardiovascular development. These defectsincluded reduced proliferation as well as precocious migrationand differentiation of neural progenitor cells. The expressionof regulators such as D-type cyclins and Notch1 was also alteredin UBR1-/-UBR2-/- embryos. We conclude that the functions ofUBR1 and UBR2 are significantly divergent, in part because ofdifferences in their expression patterns and possibly also becauseof differences in their recognition of protein substrates thatcontain degradation signals other than N-degrons.
Author contributions: J.Y.A., T.T., A.V., and Y.T.K. designed research; J.Y.A., J.W.S., T.T., M.J.L., and Y.T.K. performed research; J.Y.A. and Y.T.K. contributed new reagents/analytic tools; J.Y.A., J.W.S., T.T., M.J.L., A.V., and Y.T.K. analyzed data; and J.Y.A., A.V., and Y.T.K. wrote the paper.
Conflict of interest statement: No conflicts declared.
To whom correspondence may be addressed.
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