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PubMedDate not supplied

High expression of Jun activation domain-binding protein 1 (Jab1) is a strong prognostic marker in oral squamous cell carcinoma patients treated by UFT in combination with radiation.

Low expression of p27Kip1 is associated with disease progression and an unfavorable outcome in several malignancies, including oral squamous cell carcinoma (OSCC). In addition, the p27Kip1 protein is thought to be degraded by the Jun activation domain-binding protein 1 (Jab1). The purpose of this study was to examine whether Jab1 expression can be a useful prognostic factor in OSCC patients treated by 1 M Tegafur and 4 M uracil (UFT) in combination with radiation. Jab1 expression was investigated by immunohistochemistry in biopsy samples from 102 OSCC patients who were treated by UFT in combination with radiation. The associations of each expression with the clinicopathological characteristics and patient survival were also analyzed. A significant association was found between Jab1 expression and cervical lymph node metastasis (p=0.0004), stage of disease (p=0.0011), therapeutic effect (p=0.0133) and patient outcome (p=0.0095). The 5-year survival rates of Jab1 high- and low-expression tumors were 53.0% and 80.6%, respectively and this difference was significant (p=0.0053) by the log-rank test. Multivariate analysis revealed that reduced term survival was related to high levels of Jab1 expression (p=0.0082). These results suggest that Jab1 may be a useful prognostic factor in OSCC patients treated by UFT in combination with radiation.

Adult↗
PubMed2006

Jab1 as a mediator of nuclear export and cytoplasmic degradation of p53.

Jun activation domain-binding protein 1 (Jab1) is involved in various cellular mechanisms including development in Drosophila and mouse, cell cycle control and signal transduction pathways. Recent studies also determined that Jab1 functions as a nuclear exporter and inducer of cytoplasmic degradation for several proteins including p53, p27, capsid of West Nile virus, and Smad4/7 proteins. In particular, p53 is shown to bind to and to be exported into the cytoplasm by Jab1, which helps to maintain low levels of p53 under normal conditions. This review was undertaken in an effort to understand the biological significance of the homeostasis of p53 as maintained in the presence of Jab1. Based on our observations, we have provided potential mechanistic hypotheses for the nuclear export of p53 in coordination with Jab1 and the role of other factors in these processes.

Active Transport, Cell Nucleus↗
PubMed2002

Inositol 1,3,4-trisphosphate 5/6-kinase associates with the COP9 signalosome by binding to CSN1.

The COP9 signalosome (CSN) is a complex of eight proteins first identified as a repressor of plant photomorphogenesis. A protein kinase activity associated with the COP9 signalosome has been reported but not identified; we present evidence for inositol 1,3,4-trisphosphate 5/6-kinase (5/6-kinase) as a protein kinase associated with the COP9 signalosome. We have shown that 5/6-kinase exists in a complex with the eight-component COP9 signalosome both when purified from bovine brain and when transfected into HEK 293 cells. 5/6-kinase phosphorylates the same substrates as those of the COP9 signalosome, including IkappaBalpha, p53, and c-Jun but fails to phosphorylate several other substrates, including c-Jun 1-79, which are not substrates for the COP9-associated kinase. Both the COP9 signalosome- associated kinase and 5/6-kinase are inhibited by curcumin. The association of 5/6-kinase with the COP9 signalosome is through an interaction with CSN1, which immunoprecipitates with 5/6-kinase. In addition, the inositol kinase activity of 5/6-kinase is inhibited when in a complex with CSN1. We propose that 5/6-kinase is the previously described COP9 signalosome-associated kinase.

Amino Acid Sequence↗
PubMed2002

The GLH proteins, Caenorhabditis elegans P granule components, associate with CSN-5 and KGB-1, proteins necessary for fertility, and with ZYX-1, a predicted cytoskeletal protein.

The GLH proteins belong to a family of four germline RNA helicases in Caenorhabditis elegans. These putative ATP-dependent enzymes localize to the P granules, which are nonmembranous complexes of protein and RNA exclusively found in the cytoplasm of all C. elegans germ cells and germ cell precursors. To determine what proteins the GLHs bind, C. elegans cDNA libraries were screened by the yeast two-hybrid method, using GLHs as bait. Three interacting proteins, CSN-5, KGB-1, and ZYX-1, were identified and further characterized. GST pull-down assays independently established that these proteins bind GLHs. CSN-5 is closely related to the subunit 5 protein of COP9 signalosomes, conserved multiprotein complexes of plants and animals. RNA interference (RNAi) with csn-5 results in sterile worms with small gonads and no oocytes, a defect essentially identical to that produced by RNAi with a combination of glh-1 and glh-4. KGB-1 is a putative JNK MAP kinase that GLHs bind. A kgb-1 deletion strain has a temperature-sensitive, sterile phenotype characterized by the absence of mature oocytes and the presence of trapped, immature oocytes that have undergone endoreplication. ZYX-1 is a LIM domain protein most like vertebrate Zyxin, a cytoskeletal adaptor protein. In C. elegans, while zyx-1 appears to be a single copy gene, neither RNAi depletion nor a zyx-1 deletion strain results in an obvious phenotype. These three conserved proteins are the first members in each of their families reported to associate with germline helicases. Similar to the loss of GLH-1 and GLH-4, loss of either CSN-5 or KGB-1 causes oogenesis to cease, but does not affect the initial assembly of P granules.

Animals↗
PubMed2004

Translational regulation via 5' mRNA leader sequences revealed by mutational analysis of the Arabidopsis translation initiation factor subunit eIF3h.

Eukaryotic translation initiation factor 3 (eIF3) consists of core subunits that are conserved from yeast to man as well as less conserved, noncore, subunits with potential regulatory roles. Whereas core subunits tend to be indispensable for cell growth, the roles of the noncore subunits remain poorly understood. We addressed the hypothesis that eIF3 noncore subunits have accessory functions that help to regulate translation initiation, by focusing on the Arabidopsis thaliana eIF3h subunit. Indeed, eIF3h was not essential for general protein translation. However, results from transient expression assays and polysome fractionation indicated that the translation efficiency of specific 5' mRNA leader sequences was compromised in an eif3h mutant, including the mRNA for the basic domain leucine zipper (bZip) transcription factor ATB2/AtbZip11, translation of which is regulated by sucrose. Among other pleiotropic developmental defects, the eif3h mutant required exogenous sugar to transit from seedling to vegetative development, but it was hypersensitive to elevated levels of exogenous sugars. The ATB2 mRNA was rendered sensitive to the eIF3h level by a series of upstream open reading frames. Moreover, eIF3h could physically interact with subunits of the COP9 signalosome, a protein complex implicated primarily in the regulation of protein ubiquitination, supporting a direct biochemical connection between translation initiation and protein turnover. Together, these data implicate eIF3 in mRNA-associated translation initiation events, such as scanning, start codon recognition, or reinitiation and suggest that poor translation initiation of specific mRNAs contributes to the pleiotropic spectrum of phenotypic defects in the eif3h mutant.

5' Untranslated Regions↗
PubMed2002

COP9 signalosome components play a role in the mating pheromone response of S. cerevisiae.

A family of genetically and structurally homologous complexes, the proteasome lid, Cop9 signalosome (CSN) and eukaryotic translation initiation factor 3, mediate different regulatory pathways. The CSN functions in numerous eukaryotes as a regulator of development and signaling, yet until now no evidence for a complex has been found in Saccharomyces cerevisiae. We identified a group of proteins, including a homolog of Csn5/Jab1 and four uncharacterized PCI components, that interact in a manner suggesting they form a complex analogous to the CSN in S. cerevisiae. These newly identified subunits play a role in adaptation to pheromone signaling. Deletants for individual subunits enhance pheromone response and increase mating efficiency. Overexpression of individual subunits or a human homolog mitigates sst2-induced pheromone sensitivity. Csi1, a novel CSN interactor, exhibits opposite phenotypes. Deletants also accumulate Cdc53/cullin in a Rub1-modified form; however, this role of the CSN appears to be distinct from that in the mating pathway.

COP9 Signalosome Complex↗
PubMed2006

Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome.

DDB1, a subunit of the damaged-DNA binding protein DDB, has been shown to function also as an adaptor for Cul4A, a member of the cullin family of E3 ubiquitin ligase. The Cul4A-DDB1 complex remains associated with the COP9 signalosome, and that interaction is conserved from fission yeast to human. Studies with fission yeast suggested a role of the Pcu4-Ddb1-signalosome complex in the proteolysis of the replication inhibitor Spd1. Here we provide evidence that the function of replication inhibitor proteolysis is conserved in the mammalian DDB1-Cul4A-signalosome complex. We show that small interfering RNA-mediated knockdown of DDB1, CSN1 (a subunit of the signalosome), and Cul4A in mammalian cells causes an accumulation of p27Kip1. Moreover, expression of DDB1 reduces the level of p27Kip1 by increasing its decay rate. The DDB1-induced proteolysis of p27Kip1 requires signalosome and Cul4A, because DDB1 failed to increase the decay rate of p27Kip1 in cells deficient in CSN1 or Cul4A. Surprisingly, the DDB1-induced proteolysis of p27Kip1 also involves Skp2, an F-box protein that allows targeting of p27Kip1 for ubiquitination by the Skp1-Cul1-F-box complex. Moreover, we provide evidence for a physical association between Cul4A, DDB1, and Skp2. We speculate that the F-box protein Skp2, in addition to utilizing Cul1-Skp1, utilizes Cul4A-DDB1 to induce proteolysis of p27Kip1.

COP9 Signalosome Complex↗
PubMed2001

Protein stability: the COP9 signalosome gets in on the act.

The COP9 signalosome is a multiprotein complex somewhat similar to the lid component of the 26S proteasome. Recent studies suggest that it regulates the stability of proteins by interfering with the ubiquitin-proteasome pathway via deneddylation and phosphorylation.

COP9 Signalosome Complex↗
PubMed2001

COP9 signalosome revisited: a novel mediator of protein degradation.

The COP9 signalosome is an evolutionarily conserved multiprotein complex that was first identified as an essential complex that represses light-regulated development in Arabidopsis. The COP9 signalosome has similarity to the lid of the 19S regulatory particle of the 26S proteasome and has recently been shown to interact with SCF-type E3 ubiquitin ligases. Although its precise role in the process of protein degradation remains to be established, the COP9 signalosome is a positive regulator of E3 ubiquitin ligases that functions at least in part by mediating the deconjugation of the NEDD8/RUB-modification from the cullin subunit of SCF-type E3 complexes. Here, we discuss these recent findings, which add an additional component to the biology of substrate-specific protein degradation.

Animals↗
PubMed2006

Jasmonate signaling pathway.

Jasmonates in plants are cyclic fatty acid-derived regulators structurally similar to prostaglandins in metazoans. These chemicals mediate many of plants' transcriptional responses to wounding and pathogenesis by acting as potent regulators for the expression of numerous frontline immune response genes, including those for defensins and antifungal proteins. Additionally, the pathway is critical for fertility. Ongoing genetic screens and protein-protein interaction assays are identifying components of the canonical jasmonate signaling pathway. A massive molecular machine, based on two multiprotein complexes, SCF(COI1) and the COP9 signalosome (CNS), plays a central role in jasmonate signaling. This machine functions in vivo as a ubiquitin ligase complex, probably targeting regulatory proteins, some of which are expected to be transcriptional repressors. Some defense-related mediators, notably salicylic acid, antagonize jasmonates in controlling the expression of many genes. In Arabidopsis, NONEXPRESSOR OF PR GENES (NPR1) mediates part of this interaction, with another layer of control provided further downstream by the mitogen-activated protein kinase (MAPK) homolog MPK4. Numerous other interpathway connections influence the jasmonate pathway. Insights from Arabidopsis have shown that an allele of the auxin signaling gene AXR1, for example, reduces the sensitivity of plants to jasmonate. APETALA2 (AP2)-domain transcription factors, such as ETHYLENE RESPONSE FACTOR 1 (ERF1), link the jasmonate pathway to the ethylene signaling pathway. As progress in characterizing several new mutants (some of which are hypersensitive to jasmonic acid) augments our understanding of jasmonate signaling, the Connections Map will be updated to include this new information.

Arabidopsis↗
PubMed2003

The COP9 signalosome: regulating plant development through the control of proteolysis.

The COP9 signalosome (CSN) is a multiprotein complex that was initially identified in plants as a repressor of photomorphogenesis. It is now known to play major roles in several other developmental pathways, from auxin response to flower development. Furthermore, the COP9 signalosome shares homologies with the lid sibcomplex of the proteasome and is evolutionarily conserved from fission yeast to humans. It is important for the proper development of virtually all higher eukaryotes. In recent years, significant progress has been made in unraveling the molecular, cellular, and physiological mode of action of the COP9 signalosome. This review discusses our current understanding of the COP9 signalosome function with particular emphasis on its recently defined role in modulating a wide variety of cellular processes by regulating specific protein degradation events.

COP9 Signalosome Complex↗
PubMed2001

Interactions of the COP9 signalosome with the E3 ubiquitin ligase SCFTIRI in mediating auxin response.

The COP9 signalosome is an evolutionary conserved multiprotein complex of unknown function that acts as a negative regulator of photomorphogenic seedling development in Arabidopsis. Here, we show that plants with reduced COP9 signalosome levels had decreased auxin response similar to loss-of-function mutants of the E3 ubiquitin ligase SCFTIR1. Furthermore, we found that the COP9 signalosome and SCFTIR1 interacted in vivo and that the COP9 signalosome was required for efficient degradation of PSIAA6, a candidate substrate of SCFTIR1. Thus, the COP9 signalosome may play an important role in mediating E3 ubiquitin ligase-mediated responses.

Arabidopsis↗
PubMed2002

MPN+, a putative catalytic motif found in a subset of MPN domain proteins from eukaryotes and prokaryotes, is critical for Rpn11 function.

BACKGROUND: Three macromolecular assemblages, the lid complex of the proteasome, the COP9-Signalosome (CSN) and the eIF3 complex, all consist of multiple proteins harboring MPN and PCI domains. Up to now, no specific function for any of these proteins has been defined, nor has the importance of these motifs been elucidated. In particular Rpn11, a lid subunit, serves as the paradigm for MPN-containing proteins as it is highly conserved and important for proteasome function. RESULTS: We have identified a sequence motif, termed the MPN+ motif, which is highly conserved in a subset of MPN domain proteins such as Rpn11 and Csn5/Jab1, but is not present outside of this subfamily. The MPN+ motif consists of five polar residues that resemble the active site residues of hydrolytic enzyme classes, particularly that of metalloproteases. By using site-directed mutagenesis, we show that the MPN+ residues are important for the function of Rpn11, while a highly conserved Cys residue outside of the MPN+ motif is not essential. Single amino acid substitutions in MPN+ residues all show similar phenotypes, including slow growth, sensitivity to temperature and amino acid analogs, and general proteasome-dependent proteolysis defects. CONCLUSIONS: The MPN+ motif is abundant in certain MPN-domain proteins, including newly identified proteins of eukaryotes, bacteria and archaea thought to act outside of the traditional large PCI/MPN complexes. The putative catalytic nature of the MPN+ motif makes it a good candidate for a pivotal enzymatic function, possibly a proteasome-associated deubiquitinating activity and a CSN-associated Nedd8/Rub1-removing activity.

Amino Acid Sequence↗
PubMed2001

Molecular characterization of subunit 6 of the COP9 signalosome and its role in multifaceted developmental processes in Arabidopsis.

The COP9 signalosome is a highly conserved protein complex initially identified as a repressor of photomorphogenesis. Here, we report that subunit 6 of the Arabidopsis COP9 signalosome is encoded by a family of two genes (CSN6A and CSN6B) located on chromosomes V and IV, respectively. The CSN6A and CSN6B proteins share 87% amino acid identity and contain a MPR1p and PAD1p N-terminal (MPN) domain at the N-terminal region. The CSN6 proteins share homology with CSN5 and belong to the Mov34 superfamily of proteins. CSN6 proteins present only in the complex form and coimmunoprecipitate with other known subunits of the COP9 signalosome. Partial loss-of-function strains of the COP9 signalosome created by antisense and cosuppression with CSN6A exhibit diverse developmental defects, including homeotic organ transformation, symmetric body organization, and organ boundary definition. Protein blot analysis revealed that the defective plants accumulate significant amounts of ubiquitinated proteins, supporting the conclusion that the COP9 signalosome regulates multifaceted developmental processes through its involvement in ubiquitin/proteasome-mediated protein degradation.

Amino Acid Sequence↗
PubMed2001

PCI complexes: pretty complex interactions in diverse signaling pathways.

Three protein complexes (the proteasome regulatory lid, the COP9 signalosome and eukaryotic translation initiation factor 3) contain protein subunits with a well defined protein domain, the PCI domain. At least two (the COP9 signalosome and the lid) appear to share a common evolutionary origin. Recent advances in our understanding of the structure and function of the three complexes point to intriguing and unanticipated connections between the cellular functions performed by these three protein assemblies, especially between translation initiation and proteolytic protein degradation.

Animals↗
PubMed2003

Protein homeostasis: a degrading role for Int6/eIF3e.

Similarities between the three related "PCI" complexes--eIF3, the COP9 signalosome and the proteasome lid--have hinted at novel pathways controlling protein homeostasis. Recent experiments with fission yeast have begun to weigh in with genetic evidence.

Animals↗