Multiple Functions of Jab1 Are Required for Early Embryonic Development and Growth Potential in Mice

Abstract

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 CSNindependent 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 G 1 , and was delayed in the progression from G 0 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.

Hypoxia-Inducible Factor 1 Promoter-Induced JAB1 Overexpression Enhances Chemotherapeutic Sensitivity of Lung Cancer Cell Line A549 in an Anoxic Environment

“…And, the cell apoptosis was arrested at G 0 /G 1 phase, which was consistent to the study of Tomoda et al in some degree (Tomoda et al, 2004). They found that Jab1-/-embryonic cells lacking other CSN components expressed comparatively higher levels of p53, p27, and cyclin E, thereby resulting in impaired proliferation and accelerated apoptosis.…”

“…However, the amount of Jab1-containing small subcomplex in Jab1+/-mouse embryonic fibroblast cells was decreased, they proliferated poorly, and the cell cycle was delayed in the progression from G 0 to S phase compared with the wild-type cells. All the findings suggested that Jab1 might control cell cycle progression and cell survival via regulating multiple cell cycle signaling pathways (Tomoda et al, 2004).…”

MIF loss impairs Myc-induced lymphomagenesis

“…11 Intracellularly, MIF complexes with the Jab1/CSN5 subunit of the COP9 signalosome, 19 which regulates numerous signaling pathways involved in gene expression and cell cycle control. [20][21][22] Several studies have indicated that activation of cell proliferation by MIF is due to a functional inactivation of the p53 tumor suppressor. 17,18,23 Thus, MIF overexpression extends the lifespan of primary cells in vitro, inhibits Myc-induced p53-dependent apoptosis, and protects macrophages from NO-induced apoptosis.…”

Characterization of theVIER F-BOX PROTEINEGenes fromArabidopsisReveals Their Importance for Plant Growth and Development

“…Furthermore, it has been proposed that CSN is part of a proteasome-related complex (Peng et al, 2001(Peng et al, , 2003. Regardless of its precise molecular mode of action, it can be said that CSN acts as a global regulator of Cullin-RING E3 activities and that loss of CSN function in higher eukaryotes causes severe growth defects (Freilich et al, 1999;Lykke-Andersen et al, 2003;Schwechheimer, 2004;Tomoda et al, 2004;Dohmann et al, 2005). Since it is expected that hundreds of Cullin-RING E3 functions are impaired in csn mutants, their severe phenotype may be the result of the combined defects caused by the impaired function of individual E3 activities.…”