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Results for “COP9 Signalosome Complex”

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PubMed2006

Overexpression of Jun activation domain-binding protein 1 in nonsmall cell lung cancer and its significance in p27 expression and clinical features.

BACKGROUND: Decreased expression of p27, which is an inhibitor of cyclin-dependent kinase, is associated with cancer aggressiveness. It is believed that Jun activation domain-binding protein 1 (Jab1) plays a role in p27 degradation in a manner that is independent from the role played by S-phase kinase-associated protein 2 (Skp2). To examine the clinical significance of Jab1 in nonsmall cell lung cancer (NSCLC), the protein expression of Jab1 in tumor tissues was investigated with regard to the expression of p27 and Skp2. METHODS: The clinicopathologic features and immunohistochemical expression levels of Jab1, p27, and Skp2 proteins were studied in 138 specimens from patients who underwent surgical resection for NSCLC. Survival analyses were performed by using the Kaplan-Meier method and Cox regression models. RESULTS: High Jab1 expression (>50% of cancer cell nuclei stained) was observed in 81 specimens (59%). In Skp2-negative specimens (n = 81), an inverse correlation between the protein expression of p27 and Jab1 was observed both with the chi-square test (P = .02) and with the Mann-Whitney U test (P = .02). High Jab1 expression levels were related to poor outcomes in 118 patients who underwent complete resection, with a 5-year overall survival rate of 43.9% for patients who had high Jab1 expression and 63.1% for patients who had low Jab1 expression (P = .01). This difference was greater in patients who had Skp2-negative specimens (51.9% vs. 79.3% (P = .02), but it was not significant in patients who had Skp2-positive specimens. The multivariate analysis revealed that Jab1 expression was an independent prognostic factor for survival in patients with NSCLC (relative risk, 2.247; P = .01). CONCLUSIONS: The current results showed for the first time that high Jab1 protein expression is related to poor outcome in patients with NSCLC and that this protein may be a target of therapy in NSCLC.

Adult↗

PubMed2006

Modified p27 Kip1 is efficient in suppressing HER2-mediated tumorigenicity.

Cyclin-dependent kinase (CDK) inhibitor p27 Kip1, a haplo-insufficient tumor suppressor, is downregulated by oncogenic signal of HER2, a receptor tyrosine kinase oncogene. HER2 promotes mitogenic growth and transformation of cancer cells. HER2 signaling can enhance p27 Kip1 ubiquitination, thereby promoting p27 degradation and subsequent activation of CDK activity. p27 ubiquitination and degradation is enhanced by JAB1 binding as well as by phosphorylation on Thr187. In this study, we generated modified p27 proteins, which are mutated at Thr 187 or deleted at JAB1 binding domain. We applied these modified p27 genes as novel anticancer agents for HER2-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. Induction of p27 T187A and p27 T187A DeltaJAB inhibits HER2-activated cell growth, CDK2 activity, cell proliferation, and transformation. Significantly, a modified protein (p27 T187ADeltaJAB) reduced the tumor volume in a HER2-overexpressing tumor model efficiently. These findings demonstrate the applicability of employing modified p27 proteins as a therapeutic intervention in HER2-overexpressing cancers.

Amino Acid Substitution↗

PubMed2004

JAB1 enhances HAND2 transcriptional activity by regulating HAND2 DNA binding.

HAND2 (also known as dHAND) is a basic helix-loop-helix (bHLH) transcription factor essential for development of the heart, limbs, and neural crest-derived lineages. HAND2 expression is observed in a number of tissues derived from the neural crest, including components of the peripheral nervous system, where it has been shown to regulate sympathetic nervous system development. Here we show that HAND2 is expressed in both the sympathetic and the parasympathetic divisions of the autonomic nervous system (ANS). How HAND2 functions during development of these neuronal lineages is uncertain. An important mechanism involved in HAND2's function is its interactions with other proteins. To understand better the molecular interactions regulating HAND2 during ANS development, we employed a yeast two-hybrid screen to identify HAND2-interacting proteins. One protein identified in this screen, Jun activation domain-binding protein (JAB1), is involved in numerous cell processes, including regulation of transcription and protein turnover. We show that JAB1 binds directly to the HLH domain of HAND2 and increases HAND2 transcription-stimulating activity. However, JAB1 does not contain a transcriptional activation domain, nor does it recruit an activation domain to HAND2. Our data indicate that JAB1 augments HAND2 transcriptional activity by enhancing HAND2 DNA binding. We further show that enhanced HAND2 DNA binding is mediated through the HLH domain and not through the DNA binding domain. These results show that JAB1 regulates the transcriptional activity of HAND2 in a unique manner that may account, in part, for the apparent ability of this bHLH factor to regulate gene expression through numerous mechanisms.

Animals↗

PubMed2006

Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia.

The excitatory amino acid transporters (EAATs) are a family of plasma membrane proteins that maintain synaptic glutamate concentration by removing glutamate from the synaptic cleft. EAATs are expressed by glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4) throughout the brain. Glutamate reuptake is regulated, in part, by EAAT-interacting proteins that modulate subcellular localization and glutamate transport activity of the EAATs. Several lines of investigation support the hypothesis of glutamatergic abnormalities in schizophrenia. Previous work in our laboratory demonstrated increased expression of EAAT1 and EAAT2 transcripts in the thalamus, suggesting that alterations in synaptic glutamate levels may contribute to the pathophysiology of schizophrenia. Since EAAT-interacting proteins regulate EAAT function, directly impacting glutamatergic neurotransmission, we hypothesized that expression of EAAT-interacting proteins may also be altered in schizophrenia. Using in situ hybridization in subjects with schizophrenia and a comparison group, we detected increased expression of JWA and KIAA0302, molecules that regulate EAAT3 and EAAT4, respectively, in the thalamus in schizophrenia. In contrast, we did not find changes in the expression of transcripts for the EAAT2 and EAAT4 regulatory proteins GPS-1 and ARHGEF11. To address prior antipsychotic treatment in our schizophrenic subjects, we treated rats with haloperidol and clozapine for 4 weeks, and found changes in transcript expression of the EAAT-interacting proteins in clozapine-, but not haloperidol-, treated rats. These findings suggest that proteins associated with the regulation of glutamate reuptake may be abnormal in this illness, supporting the hypothesis of altered thalamic glutamatergic neurotransmission in schizophrenia.

Aged↗

PubMed2002

Molecular regulation of muscle cachexia: it may be more than the proteasome.

Muscle cachexia induced by sepsis, severe injury, cancer, and a number of other catabolic conditions is mainly caused by increased protein degradation, in particular breakdown of myofibrillar proteins. Ubiquitin-proteasome-dependent proteolysis is the predominant mechanism of muscle protein loss in these conditions, but there is evidence that several other regulatory mechanisms may be important as well. Some of those mechanisms are reviewed in this article and they include pre-, para-, and postproteasomal mechanisms. Among preproteasomal mechanisms, mediators, receptor binding, signaling pathways, activation of transcription factors, and modification of proteins are important. Several paraproteasomal mechanisms may influence the trafficking of ubiquitinated proteins and their interaction with the proteasome, including the expression and activity of the COP9 signalosome, the carboxy terminus of heat shock protein 70-interacting protein (CHIP) and valosin-containing protein (VCP). Finally, because the proteasome does not degrade proteins completely into free amino acids but into peptides, postproteasomal degradation of peptides by the giant protease tripeptidyl peptidase II (TPP II) and various aminopeptidases is important in muscle catabolism. Thus, multiple mechanisms and regulatory steps may influence the breakdown of ubiquitinated muscle proteins by the 26S proteasome.

Adenosine Triphosphatases↗

PubMed2002

Differential display RT-PCR analysis of enterovirus-71-infected rhabdomyosarcoma cells reveals mRNA expression responses of multiple human genes with known and novel functions.

In order to better understand cellular responses to viral infection at the transcriptional level, we employed differential display RT-PCR to analyze mRNAs from RD rhabdomyosarcoma cells following infection with a neurovirulent enterovirus 71 (EV71) strain, compared with mRNAs from uninfected cells. Of 250 expressed sequence tags (ESTs) isolated, sequenced, and identified, all were of cellular origin except 1 that was of viral origin. Of these, 156 were individual distinctive clones, comprising 45 mRNAs showing unaltered expression and 111 mRNAs exhibiting upregulation or downregulation. Of the 45 uniformly expressed mRNAs, 14 represented unknown genes. Of the 111 differentially expressed mRNAs, 63 did not match any known genes. Forty-eight of the 111 mRNAs modified by EV71 infection matched known genes, including those encoding components of cell cycle, cytoskeleton, and cell death mediators; protein degradation mediators; mitochondrial-related proteins; components of protein translation and modification; and cellular transport proteins. The altered expression profiles of representative genes were authenticated by semiquantitative RT-PCR and real-time RT-PCR. We also identified a novel alternatively spliced transcript of TRIP7 thyroid receptor interactor protein; the putative human homolog of murine mc7 mRNA predominantly expressed in the brain; and a novel mRNA similar to that encoding vacuolar protein 8 involved in protein targeting. These results underscore the applicability of the mRNA differential display technique for elucidating the expression profiles of known and even novel genes in response to cellular infection with pathogenic viruses.

Amino Acid Sequence↗

PubMed2005

Jun activation domain-binding protein 1 is required for mitotic checkpoint activation via its involvement in hyperphosphorylation of 53BP1.

PURPOSE: p53-binding protein 1 (53BP1), a participant in the DNA damage response pathway, has also been implicated in the cellular response to mitotic stress conditions. Here, we sought to broaden our understanding of the protein network surrounding 53BP1 by identifying and characterizing a 53BP1-interacting protein. METHOD: Yeast two-hybrid screening was performed to identify possible binding partners of 53BP1. To investigate the functional meaning of the interaction, knock-down cells were established by introduction of antisense construct or siRNA into HeLa cells. The hyperphosphorylation of 53BP1 after treatment with nocodazole, a microtubule-interfering agent, was monitored by immunoblotting. And the cell cycle arrest at mitotic phase was measured by flow cytometry after staining with phospho-(Ser10)-histone H3 antibody. RESULTS: Jun activation domain-binding protein 1 (Jab1) was identified as a 53BP1-binding protein, and the interaction between them was confirmed to occur in mammalian cells. We found that nocodazole-induced 53BP1 hyperphosphorylation was abolished in Jab1 knock-down cells. In addition, ectopic overexpression of Jab1 augmented 53BP1 hyperphosphorylation. On the cellular level, Jab1 knock-down cells exhibited reduced mitotic arrest upon exposure to nocodazole, resulting in cellular resistance to the drug. CONCLUSION: Taken together, these results suggest that Jab1 is required for the hyperphosphorylation of 53BP1 upon mitotic stress conditions and is involved in proper activation of mitotic checkpoint mechanism. Our study also suggests the possibility that modulation of Jab1 activity may be an intriguing approach for enhancing the efficacy of microtubule-interfering anticancer drugs.

Antineoplastic Agents↗

PubMed1996

The Drosophila gene alien is expressed in the muscle attachment sites during embryogenesis and encodes a protein highly conserved between plants, Drosophila and vertebrates.

We have found a novel gene (alien) that is expressed exclusively in the muscle attachment sites (apodemes) during embryogenesis in Drosophila. Antibodies raised against the Alien protein enable us to follow the developing attachments from state 11/12 until stage 16/17. The coding region of the Drosophila alien gene is highly conserved to a gene of unknown function, isolated from a plant (Loo et at., 1995), and to the human TRIP15 gene (Lee et al., 1995). Searching for thyroid receptor interacting proteins, TRIP15 was isolated as a negative regulator. Whether there is a functional correlation to Alien remains to be analyzed. Alien expression is independent of muscle formation, as shown in rolling stone mutant embryos. Even in twist and snail mutants, lacking mesodermal development, alien expression is fairly normal, showing a rather autonomous development of the apodemes. The conservation of alien suggests an important role in differentiation.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2006

Molecular cloning and characterization of human Aph2 gene, involved in AP-1 regulation by interaction with JAB1.

A human Aph2 gene (hAph2) was identified and cloned from a human placenta cDNA library. Bioinformatics analysis revealed hAPH2 protein shares 96% identity with mouse APH2 and contains a zf-DHHC domain (148-210aa), which is always involved in protein-protein or protein-DNA interaction. Differential expression patterns of hAph2 mRNA were observed in normal human tissues. Yeast two-hybrid screening found another hAPH2-interacting protein JAB1. The zf-DHHC domain of hAPH2 and the C-terminal of JAB1 were confirmed to be critical for the interaction. Fused with GFP and expressed in COS-7, NIH/3T3 and SMMC-7721 cell lines, hAPH2 showed predominant distribution in the cytoplasm and co-localized with JAB1 around the nucleus. Furthermore, overexpression of hAPH2 could increase apoptosis of COS-7 cells and negatively regulate JAB1-induced activation of AP-1 in a concentration dependent manner. The expression level of c-jun was also down-regulated by overexpression of hAPH2 in COS-7 cells. These data showed some basic characterization and function of hAph2 (hAPH2), dependent or independent with JAB1.

Amino Acid Sequence↗

PubMed2005

Interaction of the stress protein p8 with Jab1 is required for Jab1-dependent p27 nuclear-to-cytoplasm translocation.

p8 is an 80 amino-acid polypeptide identified because of its remarkable over-expression in the stressed pancreas. This protein, apparently devoid of enzymatic activity, is a powerful regulator of several intracellular pathways, suggesting that it has to interact with several molecular partners to modulate their activity. We used two-hybrid screening of a pre-transformed human testes cDNA library to identify some of these partners. One of them was the multifunctional protein Jab1, its interaction with p8 being confirmed by His6-pull down and co-immunoprecipitation assays. In addition, we could show that the two proteins co-localized in the cell. Our functional data demonstrate that Jab1 requires direct interaction with p8 to induce the translocation of p27 from nucleus to cytoplasm and its subsequent degradation. Experiments showing that the knock-down of p8 expression results in a strong inhibition of Jab1 activity confirmed that the mechanism by which Jab1 promotes cell growth by decreasing p27 level is p8-dependent.

Active Transport, Cell Nucleus↗

PubMed2005

Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity.

Macrophage migration inhibitory factor (MIF) is a 12.5 kD polypeptide that serves as a critical regulator of cell functions such as gene expression, proliferation or apoptosis. However, the signal transduction pathways through which MIF takes part in cellular regulation are only incompletely understood. MIF leads to CD74-dependent "sustained" activation of ERK1/2 MAPK, but MIF's role in "transient" ERK activation and the involved upstream pathways are unknown. Here we report that the transient ERK pathway was markedly activated by MIF. This effect involved the phosphorylation and activation of Raf-1, MEK, ERK, and Elk-1. Of note, rapid and transient ERK phosphorylation by MIF was measurable in MIF-deficient cells, suggesting that MIF acted in a non-autocrine fashion. Applying the inhibitor genistein, a tyrosine kinase (TPK) activity was identified as a critical upstream signalling event in MIF-induced transient ERK signalling. Experiments using the Src kinase inhibitor PP2 indicated that the involved TPK was a Src-type tyrosine kinase. A role for an upstream Src kinase was proven by applying Src-deficient cells which did not exhibit transient ERK activation upon treatment with MIF, but in which MIF-induced ERK signalling could be restored by re-expressing Src. Intriguingly, JAB1/CSN5, a signalosome component, cellular binding protein of MIF and regulator of cell proliferation and survival, had a marked, yet dual, effect on MIF-induced ERK signalling. JAB1 overexpression inhibited sustained, but not transient, ERK phosphorylation. By contrast, JAB1-knock-down by siRNA revealed that minimum JAB1 levels were necessary for transient activation of ERK by MIF. In conclusion, MIF rapidly and transiently activates the ERK pathway, an effect that has not been recognized previously. This signalling pathway involves the upstream activation of a Src-type kinase and is co-regulated by the cellular MIF binding protein JAB1/CSN5. Our study thus has unravelled a novel MIF-driven signalling pathway and an intricate regulatory system involving extra- and possibly intracellular MIF, and which likely critically participates in controlling cell proliferation and survival.

Animals↗

PubMed2004

The transcription factor FUSCA3 controls developmental timing in Arabidopsis through the hormones gibberellin and abscisic acid.

Although plants continually produce different organs throughout their life cycle, little is known about the factors that regulate the timing of a given developmental program. Here we report that the restricted expression of FUS3 to the epidermis is sufficient to control foliar organ identity in Arabidopsis by regulating the synthesis of two hormones, abscisic acid and gibberellin. These hormones in turn regulate the rates of cell cycling during organ formation to determine whether an embryonic or adult leaf will emerge. We also show that FUS3 expression is influenced by the patterning hormone, auxin, and therefore acts as a nexus of hormone action during embryogenesis. The identification of lipophillic hormones downstream of a heterochronic regulator in Arabidopsis has parallels to mechanisms of developmental timing in animals and suggests a common logic for temporal control of developmental programs between these two kingdoms.

Abscisic Acid↗

PubMed2004

ReFUSing to grow up.

At germination, plants must coordinate the exit from dormancy and the start of vegetative growth. In this issue of Developmental Cell, Gazzarrini et al. show that FUSCA3 plays a critical role in regulating hormone levels to synchronize the transition from embryonic to vegetative growth in Arabidopsis.

Arabidopsis↗

PubMed2006

Depletion of Jab1 inhibits proliferation of pancreatic cancer cell lines.

Jab1 overexpression is observed in many human cancers, but its physiological significance remains to be investigated. We reduced the level of Jab1 expression in pancreatic cancer cell lines, MIA PaCa-2 and PANC-1 by the RNA interference and found that Jab1-knockdown resulted in impaired cell proliferation and enhanced apoptosis regardless of the genotype of the tumor suppressor p53. This growth inhibition was rescued by the introduction of siRNA-resistant mouse Jab1 cDNA. Jab1-knocked-down cells expressed a higher level of c-myc, and additional depletion of c-myc rescued cells from Jab1-knockdown-mediated growth suppression. Thus, Jab1 overexpression contributes to pancreatic cancer cell proliferation and survival. Jab1 could be a novel target in cancer therapy.

Amino Acid Sequence↗

PubMed2003

Mixed lineage kinase 2 enhances trans-repression of Alien and nuclear receptors.

Alien was previously identified as a corepressor for the thyroid hormone receptor (TR) and DAX-1 which belong both to the superfamily of nuclear receptors. Here, we isolated the mixed lineage kinase 2 (MLK2) as an interacting partner for the corepressor Alien using a yeast two hybrid screen. MLK2 is an upstream activator of JNKs and activation of MLK2-mediated signaling cascades play roles in neurodegenerative and apoptotic mechanisms in the central nervous system. MLK2 has been shown to be localized both in the cytoplasm and cell nucleus. We confirmed the Alien-MLK2 interaction using GST pull-down experiments and also show that MLK2 is able to phosphorylate Alien in immune-kinase assays. Functional analyses revealed that Alien, DAX-1 and thyroid hormone receptor mediated transcriptional silencing is strongly enhanced in the presence of active MLK2. Since MAP kinase signaling pathways are important mediators of cellular responses to a wide variety of stimuli, our data suggest that signaling pathways not only regulate transactivation but also enhancement of transcriptional silencing. This novel cross-talk may represent a link between MLK2-mediated signaling and transcriptional repression of target genes during neuronal differentiation processes.

COP9 Signalosome Complex↗

PubMed2004

JAB1 participates in unfolded protein responses by association and dissociation with IRE1.

Recent papers have reported that neuronal death in patients with Alzheimer's disease, Parkinson's disease, and cerebral ischemia has its origin in the endoplasmic reticulum (ER). IRE1alpha is one of the ER stress transducers that detect the accumulation of unfolded proteins in the ER. IRE1alpha mediates two major cellular responses, which are the unfolded protein response (UPR), a defensive response, and apoptosis that leads to cell death. However, little is known about the regulatory mechanisms that select between the UPR and apoptosis. We identified Jun activation domain-binding protein-1 (JAB1) as a molecule that interacts with IRE1alpha using a yeast two-hybrid system. We demonstrated that JAB1 binds to IRE1alpha in the absence of stress, but that binding is decreased by ER stress inducers. Moreover, mutant JAB1 down-regulates the UPR signaling pathway through tight binding with IRE1alpha. These results suggested that JAB1 may act as a key molecule in selecting the UPR or cell death by association and dissociation with IRE1alpha.

Antibodies↗

PubMed2005

The neuronal POU transcription factor Brn-2 interacts with Jab1, a gene involved in the onset of neurodegenerative diseases.

Brain-2 (Brn-2), a Class III POU transcription factor, plays an important role in the development of the neocortex and the establishment of neural cell lineage. Here we performed a yeast two-hybrid screening to identify the Brn-2 binding proteins. We obtained Jun-activation-domain-binding protein 1 (Jab1) as a new Brn-2 binding protein. Direct interaction between Brn-2 and Jab1 was confirmed by using a surface plasmon resonance biosensor. Considering the involvement of Jab1 in the onset of the neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, the interaction between Brn-2 and Jab1 may provide some insights into the understanding of neuronal development and neurodegenerative diseases.

Animals↗

PubMed2005

The Arabidopsis inositol 1,3,4-trisphosphate 5/6 kinase, AtItpk-1, is involved in plant photomorphogenesis under red light conditions, possibly via interaction with COP9 signalosome.

The COP9 signalosome (CSN) plays important roles in multifaceted cellular processes. Study has shown that inositol 1,3,4-trisphosphate 5/6 kinase (5/6 kinase) interacts with CSN in mammalian cells. However, the biological function of the interaction still remains unknown. Here, we report that the Arabidopsis inositol 1,3,4-trisphosphate 5/6 kinase (AtItpk-1) is also associated with CSN and involved in photomorphogenesis under red light (RL) conditions, as demonstrated by co-immunoprecipitation of AtItpk-1 with CSN and characterization of the atitpk-1 mutants. Expression analysis showed that AtItpk-1 had the same sub-cellular localization and organ expression pattern as CSN. Furthermore, autophosphorylation analysis showed that AtItpk-1 has protein kinase activity. Under RL, the atitpk-1 mutants exhibited phenotype slightly similar with that of the csn mutants, indicating that 5/6 kinase might be involved in the same developmental pathway as CSN. This study suggests that AtItpk-1 may function as a protein kinase that is involved in photomorphogenesis possibly via interaction with COP9 signalosome under red light.

Arabidopsis↗