The mouse polyubiquitin gene UbC is essential for fetal liver development, cell-cycle progression and stress tolerance.
UbC is one of two stress-inducible polyubiquitin genes in mammals and is thought to supplement the constitutive UbA genes in maintaining cellular ubiquitin (Ub) levels during episodes of cellular stress. We have generated mice harboring a targeted disruption of the UbC gene. UbC(-/-) embryos die between embryonic days 12.5 and 14.5 in utero, most likely owing to a severe defect in liver cell proliferation. Mouse embryonic fibroblasts from UbC(-/-) embryos exhibit reduced growth rates, premature senescence, increased apoptosis and delayed cell-cycle progression, with slightly, but significantly, decreased steady-state Ub levels. UbC(-/-) fibroblasts are hypersensitive to proteasome inhibitors and heat shock, and unable to adequately increase Ub levels in response to these cellular stresses. Most, but not all of the UbC(-/-) phenotypes can be rescued by providing additional Ub from a poly hemagglutinin-tagged Ub minigene expressed from the Hprt locus. We propose that UbC is regulated by a process that senses Ub pool dynamics. These data establish that UbC constitutes an essential source of Ub during cell proliferation and stress that cannot be compensated by other Ub genes.
Ryu
Kwon-Yul
KY
Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA.
Maehr
René
R
Gilchrist
Catherine A
CA
Long
Michael A
MA
Bouley
Donna M
DM
Mueller
Britta
B
Ploegh
Hidde L
HL
Kopito
Ron R
RR
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology; D047109:Fetal Development / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020043:Genes, Essential / Q000235:genetics; D008099:Liver / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D025822:Ubiquitin C / Q000235:genetics*
D025822:Ubiquitin C