Multiple functions of Jab1 are required for early embryonic development and growth potential in mice.
Jab1 interacts with a variety of signaling molecules and regulates their stability in mammalian cells. As the fifth component of the COP9 signalosome (CSN) complex, Jab1 (CSN5) plays a central role in the deneddylation of the cullin subunit of the Skp1-Cullin-F box protein ubiquitin ligase complex. In addition, a CSN-independent function of Jab1 is suggested but is less well characterized. To elucidate the function of Jab1, we targeted the Jab1 locus by homologous recombination in mouse embryonic stem cells. Jab1-null embryos died soon after implantation. Jab1-/- embryonic cells, which lacked other CSN components, expressed higher levels of p27, p53, and cyclin E, resulting in impaired proliferation and accelerated apoptosis. Jab1 heterozygous mice were healthy and fertile but smaller than their wild-type littermates. Jab1+/- mouse embryonic fibroblast cells, in which the amount of Jab1-containing small subcomplex, but not that of CSN, was selectively reduced, proliferated poorly, showed an inefficient down-regulation of p27 during G1, and was delayed in the progression from G0 to S phase by 3 h compared with the wild-type cells. Most interestingly, in Jab1+/- mouse embryonic fibroblasts, the levels of cyclin E and deneddylated Cul1 were unchanged, and p53 was not induced. Thus, Jab1 controls cell cycle progression and cell survival by regulating multiple cell cycle signaling pathways.
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
Kiichiro
K
Tomoda
Noriko
N
Yoneda-Kato
Akihisa
A
Fukumoto
Shinya
S
Yamanaka
Jun-Ya
JY
Kato
D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000737:chemistry; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D044783:F-Box Proteins / Q000737:chemistry; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D046912:Multiprotein Complexes; D009154:Mutation; D010447:Peptide Hydrolases; D011506:Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D044786:S-Phase Kinase-Associated Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex