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PubMed1999

The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators.

The proto-oncoprotein Bcl-3 is a member of the IkappaB family and is present predominantly in the nucleus. To gain insight into specific nuclear functions of Bcl-3 we have isolated proteins that interact with its ankyrin repeat domain. Using the yeast two-hybrid-system we identified four novel binding partners of Bcl-3 in addition to NF-kappaB p50 and p52, previously known to associate with Bcl-3. The novel Bcl-3 interactors Jab1, Pirin, Tip60 and Bard1 are nuclear proteins which also bind to other transcription factors including c-Jun, nuclear factor I (NFI), HIV-1 Tat or the tumor suppressor and PolII holoenzyme component Brca1, respectively. Bcl-3, p50, and either Bard1, Tip60 or Pirin are sequestered into quarternary complexes on NF-kappaB DNA binding sites, whereas Jab1 enhances p50-Bcl-3-DNA complex formation. Furthermore, the histone acetylase Tip60 enhances Bcl-3-p50 activated transcription through an NF-kappaB binding site, indicating that quarternary complexes containing Bcl-3 interactors modulate NF-kappaB driven gene expression. These data implicate Bcl-3 as an adaptor between NF-kappaB p50/p52 and other transcription regulators and suggest that its gene activation function may at least in part be due to recruitment of the Tip60 histone actetylase.

Acetyltransferases↗
PubMed2002

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway.

VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 finger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was confirmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.

3T3 Cells↗
PubMed1996

A new group of conserved coactivators that increase the specificity of AP-1 transcription factors.

The Jun proteins are nuclear proteins that combine with Fos proteins to form a gene-regulatory protein, AP-1. They have highly conserved DNA-binding and dimerization domains, resulting in almost identical sequence-recognition properties. Nevertheless, there are many indications that each Jun protein activates a distinct and only partially overlapping set of AP-1 target genes. Using the more variable activation domain of c-Jun as a bait, we identified a protein, JAB1, that interacts with c-Jun and JunD, but not with JunB or v-Jun. As a result, JAB1 selectively potentiates transactivation by only c-Jun or JunD. In vitro, JAB1 specifically stabilizes complexes of c-Jun or JunD with AP-1 sites and does not affect binding of either JunB or v-Jun. The amino-terminal half of JAB1 is very similar to the amino terminal region of Pad1 from fission yeast, which was identified genetically as a coactivator of a subset of AP-1 target genes. JAB1 and Pad1 are also functionally interchangeable. They define a new group of coactivators that increase the specificity of target gene activation by AP-1 proteins.

Amino Acid Sequence↗
PubMed2002

Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1).

PGP9.5 (UCH-L1) is a member of the ubiquitin C-terminal hydrolase (UCH) family of proteins that is expressed in neuronal tissues. Our previous studies have shown that PGP9.5 was highly expressed in primary lung cancers and lung cancer cell lines. Additionally, the frequency of PGP9.5 over expression increases with tumor stage, indicating that PGP9.5 may play a role in lung cancer tumorigenesis. We used the yeast two-hybrid system to identify proteins that interact with PGP9.5. We show that PGP9.5 interacts with at least three proteins, one of which is JAB1, a Jun activation domain binding protein that can bind to p27(Kip1) and is involved in the cytoplasmic transportation of p27(Kip1) for its degradation. We also show that PGP9.5 is associated with JAB1 in vitro and in vivo; and that both proteins can be a part of a heteromeric complex containing p27(Kip1) in the nucleus in lung cancer cells. Furthermore, under serum-restimulation, nuclear translocation of both PGP9.5 and JAB1 coincides with a reduced level of p27(Kip1) in the nucleus. In contrast, when cells are contact inhibited, both PGP9.5 and JAB1 became more perinuclear and cytoplasmic in localization while p27(Kip1) was present only in the nucleus. Therefore, PGP9.5 may contribute to p27(Kip1) degradation via its interaction and nuclear translocation with JAB1.

Active Transport, Cell Nucleus↗
PubMed1999

Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1.

The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27Kip1 is an essential participant in this regulation both in vitro and in vivo. Although mutations in p27Kip1 are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas, suggesting that disruption of the p27Kip1 regulatory mechanisms contributes to neoplasia. The abundance of p27Kip1 in the cell is determined either at or after translation, for example as a result of phosphorylation by cyclinE/Cdk2 complexes, degradation by the ubiquitin/proteasome pathway, sequestration by unknown Myc-inducible proteins, binding to cyclinD/Cdk4 complexes, or inactivation by the viral E1A oncoprotein. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27Kip1 and show here that overexpression of p38 in mammalian cells causes the translocation of p27Kip1 from the nucleus to the cytoplasm, decreasing the amount of p27Kip1 in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27Kip1-mediated arrest in the G1 phase of the cell cycle and markedly reduces their dependence on serum. Our findings indicate that p38 functions as a negative regulator of p27Kip1 by promoting its degradation.

3T3 Cells↗
PubMed2001

The constitutive photomorphogenesis 9 signalosome directs vascular endothelial growth factor production in tumor cells.

Angiogenesis is a prerequisite for solid tumor growth and metastasis. Elucidation of the signaling pathways that control tumor angiogenesis constitutes the basis for a rational antiangiogenic tumor therapy. Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN). The CSN is a kinase complex that cooperates with the ubiquitin/26S proteasome system in regulating the stability of proteins involved in signal transduction. VEGF expression is controlled by the transcription factors activator protein (AP)-1, AP-2, SP-1, and hypoxia-inducible factor 1. Inhibition of CSN kinase activity by 50 microM curcumin for 2 h decreases the cellular c-Jun concentration, resulting in a reduction of the VEGF production by approximately 75%. The removal of the inhibitor from the cells led to a time-dependent recovery of endogenous c-Jun that is paralleled by increasing VEGF production. Elevated cellular CSN activity induced by CSN subunit 2 overexpression causes increased VEGF production in HeLa cells. A competitor of CSN-dependent c-Jun phosphorylation, the NH(2)-terminal c-Jun fragment Deltac-Jun(1-226), inhibits VEGF production in HeLa cells. The transcription factors AP-2 and SP-1 act independently of the CSN. They contribute less than a quarter to basal VEGF production. Under our experimental conditions, hypoxia-inducible factor 1alpha protein was not detected. Overexpression of the tumor suppressor p53 reduces VEGF production in HeLa cells. p53 competes with c-Jun for CSN-specific phosphorylation with the consequence of c-Jun destabilization. We conclude that CSN-directed c-Jun signaling mediates high VEGF production in HeLa and HL-60 cells. The data provide an explanation for the known antiangiogenic and antitumorigenic activities of curcumin. Because the CSN regulates the major part of VEGF production in the tested tumor cells, it constitutes a potentially important target for tumor therapy.

COP9 Signalosome Complex↗
PubMed2002

Deletion mutants in COP9/signalosome subunits in fission yeast Schizosaccharomyces pombe display distinct phenotypes.

The COP9/signalosome complex is highly conserved in evolution and possesses significant structural similarity to the 19S regulatory lid complex of the proteasome. It also shares limited similarity to the translation initiation factor eIF3. The signalosome interacts with multiple cullins in mammalian cells. In the fission yeast Schizosaccharomyces pombe, the Csn1 subunit is required for the removal of covalently attached Nedd8 from Pcu1, one of three S. pombe cullins. It remains unclear whether this activity is required for all the functions ascribed to the signalosome. We previously identified Csn1 and Csn2 as signalosome subunits in S. pombe. csn1 and csn2 null mutants are DNA damage sensitive and exhibit slow DNA replication. Two further putative subunits, Csn4 and Csn5, were identified from the S. pombe genome database. Herein, we characterize null mutations of csn4 and csn5 and demonstrate that both genes are required for removal of Nedd8 from the S. pombe cullin Pcu1 and that their protein products associate with Csn1 and Csn2. However, neither csn4 nor csn5 null mutants share the csn1 and csn2 mutant phenotypes. Our data suggest that the subunits of the signalosome cannot be considered as a distinct functional unit and imply that different subunits of the signalosome mediate distinct functions.

COP9 Signalosome Complex↗
PubMed2006

Jab1 induces the cytoplasmic localization and degradation of p53 in coordination with Hdm2.

The biological mechanisms for maintaining the basal level of p53 in normal cells require nuclear exclusion and cytoplasmic degradation. Here, we showed that Jab1 facilitates p53 nuclear exclusion and its subsequent degradation in coordination with Hdm2. p53 was excluded from the nucleus in the presence of Jab1; this exclusion was prevented by leptomycin B treatment. Nuclear export of p53 was accompanied by a decrease in the levels of p53, as well as of its target proteins, which include p21 and Bax. Domain analyses of Jab1 showed that the N-terminal domain, 1-110, was capable of inducing cytoplasmic translocation of p53. Furthermore, 110-191 was required to facilitate the degradation of p53. Neither of these mutants incorporated into the CSN complex, indicating that Jab1 could affect the levels of p53 independent of intact CSN complex. Conversely, Jab1 was incapable of translocating and degrading two p53 mutants, W23S and 6KR, neither of which could be modified by Hdm2. Moreover, Jab1 did not affect the cellular localization or protein levels of p53 in p53 and Hdm2 double-null mouse embryo fibroblasts. We further observed that the ablation of endogenous Jab1 by small interfering RNA prevented Hdm2-mediated p53 nuclear exclusion. Under stressed conditions, which could sequester Hdm2 in its inactive state, Jab1 did not affect p53. Our studies implicate that Jab1 is required to remove post-translationally modified p53 and provide a novel target for p53-related cancer therapies.

Animals↗
PubMed2000

Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome.

Interferon consensus sequence-binding protein (ICSBP) is a member of the interferon regulatory factors (IRF) that has a pivotal role in mediating resistance to pathogenic infections in mice and in promoting the differentiation of myeloid cells. ICSBP exerts some of its transcriptional activities via association with other factors that enable its binding to a variety of promoters containing DNA composite elements. These interactions are mediated through a specific COOH-terminal domain termed IAD (IRF association domain). To gain a broader insight of the capacity of ICSBP to interact with other factors, yeast two-hybrid screens were performed using ICSBP-IAD as a bait against a B-cell cDNA library. Trip15 was identified as a specific interacting factor with ICSBP in yeast cells, which was also confirmed by in vitro glutathione S-transferase pull-down assays and by coimmunoprecipitation studies in COS7 cells. Trip15 was recently identified as a component of the COP9/signalosome (CSN) complex composed of eight evolutionary conserved subunits and thus termed CSN2. This complex has a role in cell-signaling processes, which is manifested by its associated novel kinase activity and by the involvement of its subunits in regulating multiple cell-signaling pathways and cell-cycle progression. We show that in vitro association of ICSBP with the CSN leads to phosphorylation of ICSBP at a unique serine residue within its IAD. The phosphorylated residue is essential for efficient association with IRF-1 and thus for the repressor activity of ICSBP exerted on IRF-1. This suggests that the CSN has a role in integrating incoming signals that affect the transcriptional activity of ICSBP.

3T3 Cells↗
PubMed2002

Jab1 co-activation of c-Jun is abrogated by the serine 10-phosphorylated form of p27Kip1.

The cyclin-dependent kinase (cdk) inhibitor p27(Kip1) is a central mediator in the imposition and maintenance of quiescence through the sequestration of G(1)-specific cyclin-cdk complexes. Previous studies have implicated the c-Jun co-activator protein Jab1 as a regulator of intracellular p27(Kip1) levels. Jab1 has been reported to interact with p27(Kip1) and cause its translocation to the cytoplasm as a prelude to the degradation of the cdk inhibitor. Here we describe experiments that showing phosphorylation of p27(Kip1) at serine 10 leads to the suppression of Jab1 levels with the concomitant inhibition of c-Jun-dependent transcription. This repression is minimized upon quiescence exit through the rapid and preferential loss of the serine 10-phosphorylated form of p27(Kip1) following serum stimulation. Our results, therefore, demonstrate an additional role for p27(Kip1) in the modulation of c-Jun-dependent transcription via Jab1.

3T3 Cells↗
PubMed2001

The fission yeast COP9/signalosome is involved in cullin modification by ubiquitin-related Ned8p.

BACKGROUND: The function of the fission yeast cullins Pcu1p and Pcu4p requires modification by the ubiquitin-related peptide Ned8p. A recent report by Lyapina et al. shows that the COP9/signalosome (CSN), a multifunctional eight subunit complex, regulates Ned8p modification of Pcu1p. Disruption of caa1/csn1, which encodes subunit 1 of the putative S. pombe CSN, results in accumulation of Pcu1p exclusively in the modified form. However, it remained unclear whether this reflects global control of all cullins by the entire CSN complex. RESULTS: We demonstrate that multiple CSN subunits control Ned8p modification of Pcu3p, another fission yeast cullin, which, in complex with the RING domain protein Pip1p, forms a ubiquitin ligase that functions in cellular stress response. Pcu3p is modified by Ned8p on Lys 729 and accumulates exclusively in the neddylated form in cells lacking the CSN subunits 1, 3, 4, and 5. These CSN subunits co-elute with Pcu3p in gel filtration fractions corresponding to approximately 550 kDa and specifically bind both native and Ned8p-modified Pcu3p in vivo. While CSN does not influence the subcellular localization of Pcu3p, Pcu3p-associated in vitro ubiquitin ligase activity is stimulated in the absence of CSN. CONCLUSIONS: Taken together, our data suggest that CSN is a global regulator of Ned8p modification of multiple cullins and potentially other proteins involved in cellular regulation.

COP9 Signalosome Complex↗
PubMed2004

Amplification and overexpression of genes in 17p11.2 ~ p12 in osteosarcoma.

We summarize and briefly discuss recent findings with respect to the amplification and overexpression of candidate oncogenes in 17p11.2 ~p12 in high-grade osteosarcomas. Amplification of this region occurs in about 25% of cases. The amplification profiles are often complex and suggest the involvement of more than one oncogene. The 17p11.2 ~ p12 region harbors many low-copy repeats (LCRs). We propose LCR-mediated repeated duplication by mitotic nonallelic homologous recombination as mechanism for the generation of the amplifications in this region. Genes PMP22 and COPS3 and three expressed sequence tags from within 17p11.2 ~ p12 have been found to be frequently overexpressed and consistently overexpressed after amplification, which identifies them as candidate oncogenes in this region. Overexpression of COPS3 has been linked to TP53 protein degradation and, being equivalent to TP53 mutation, the induction of genomic instability, which frequently occurs in high-grade osteosarcoma. These findings may serve as a framework for future work aimed to identify the causative oncogenes in 17p11.2 ~p12, to clarify the mechanism of their amplification, and to determine their importance in osteosarcoma tumorigenesis.

Bone Neoplasms↗
PubMed2002

Conservation of the COP9/signalosome in budding yeast.

BACKGROUND: The COP9/signalosome (CSN), a multiprotein complex consisting of eight subunits, is implicated in a wide variety of regulatory processes including cell cycle control, signal transduction, transcriptional activation, and plant photomorphogenesis. Some of these functions have been linked to CSN-associated enzymes, including kinases and an activity that removes the ubiquitin-like protein NEDD8/Rub1p from the cullin subunit of E3 ligases. CSN is highly conserved across species from fission yeast to humans, but sequence comparison has failed to identify the complex in budding yeast, except for a putative CSN5 subunit called Rri1p. RESULTS: We show that disruption of four budding yeast genes, PCI8 and three previously uncharacterized ORFs, which encode proteins interacting with Rrr1p/Csn5p, each results in the accumulation of the cullin Cdc53p exclusively in the Rub1p-modified state. This phenotype, which resembles that of fission yeast csn mutants, is due to a biochemical defect in deneddylation that is complemented by wild-type cell lysate and by purified human CSN in vitro. Although three of the four genes encode proteins with PCI domains conserved in metazoan CSN proteins, their disruption does not confer the DNA damage sensitivity described in some fission yeast csn mutants. CONCLUSIONS: Our studies present unexpected evidence for the conservation of a functional homologue of the metazoan CSN, which mediates control of cullin neddylation in budding yeast.

Animals↗
PubMed2005

The csnD/csnE signalosome genes are involved in the Aspergillus nidulans DNA damage response.

The signalosome (CSN) is a conserved multiprotein complex involved in regulation of eukaryotic development and is also required to activate ribonucleotide reductase for DNA synthesis. In Aspergillus nidulans, csnD/csnE are key regulators of sexual development. Here, we investigated whether the csnD/csnE genes are involved in the DNA damage response in this fungus. The growth of the csnD/csnE deletion mutants was reduced by subinhibitory concentrations of hydroxyurea, camptothecin, 4-nitroquinoline oxide, and methyl methanesulfonate. A. nidulans increases csnD/csnE mRNA levels when it is challenged by different DNA-damaging agents. There is no significant transcriptional induction of the csnE promoter fused with lacZ gene in the presence of DNA-damaging agents, suggesting that increased mRNA accumulation is due to increased mRNA stability. Septation was not inhibited in the csnD/csnE deletion mutants while DeltauvsB DeltacsnE presented an increase in septation upon DNA damage caused by methyl methanesulfonate, suggesting that uvsB(ATR) and csnE genetically interact during checkpoint-dependent inhibition of septum formation. The double DeltacsnD/DeltacsnE DeltanpkA mutants were more sensitive to DNA-damaging agents than were the respective single mutants. Our results suggest that csnD/csnE genes are involved in the DNA damage response and that NpkA and UvsB(ATR) genetically interact with the signalosome.

Aspergillus nidulans↗
PubMed1999

Isolation and mapping of rFUS6, a rice orthologue of Arabidopsis thaliana FUS6.

COP9 complex is one of the most important components that act in repressing photomorphogenesis in Arabidopsis thaliana. FUS6 has been identified as one of eight subunits of the COP9 complex in Arabidopsis. Using Arabidopsis Fus6 cDNA as a probe, we screened a rice root cDNA library and a rice genomic library. A 1730-bp cDNA was obtained, which has an open reading frame corresponding to 441-amino-acid. This 441 amino acids putative protein has 67% identity with Arabidopsis COP11/FUS6 (AtFUS6) and 40% identity with human GPS1, an AtFUS6 orthologue. So we designated this novel gene as rFUS6. The 6.2-kb genomic sequence of rFUS6 was also obtained. Sequence comparison showed that the rFUS6 gene had six exons and five introns. Sequence inspection of the 5'-flanking region revealed the presence of some potential light-regulated cis-elements such as a G-box, GT-1 binding sites, and a TGACG motif. Southern hybridization with rice total DNA showed that rFUS6 was perhaps a single copy gene. The rFUS6 locus was mapped by hybridization with a rice BAC library membrane and the results showed that rFUS6 had a locus at 16.3 cM of chromosome 1.

Amino Acid Sequence↗
PubMed2006

Identification and characterization of a proteolysis-resistant fragment containing the PCI domain in the Arabidopsis thaliana INT6/eIF3e translation factor.

The PCI domain comprises approx 200 amino acids and is found in subunits of the eukaryotic translation initiation factor 3 (eIF3), the 26S proteasome and the COP9/signalosome complexes. The PCI domain is involved in protein-protein interaction, and mouse INT6 truncated proteins lacking the PCI domain show cell malignanttransforming activity. In this work, the Arabidopsis thaliana INT6/eIF3e (AtINT6) protein was dissected using limited proteolysis, and a protease-resistant fragment containing the PCI domain was identified. Based on mass spectrometry analyses of the protease-resistant fragments and on secondary structure prediction, AtINT6-truncated proteins were cloned and expressed in Escherichia coli. Stability studies using thermal unfolding followed by circular dichroism revealed a midpoint transition temperature of 44 degrees C for the full-length AtINT6 protein, whereas the truncated proteins comprising residues 125-415 (AtINT6TR2) and 172-415 (AtINT6TR3) showed transition temperatures of 49 and 58 degrees C, respectively. AtINT6TR3 contains the PCI domain with additional amino acids at the N and C termini. It shows high solubility, and together with the high thermal stability, should facilitate further characterization of the PCI domain structure, which is important to understand its function in protein- protein interaction.

Amino Acid Motifs↗
PubMed2004

Overexpression through amplification of genes in chromosome region 17p11.2 approximately p12 in high-grade osteosarcoma.

Osteosarcomas are malignant tumors of the bone that are characterized by complex genetic changes, including loss and amplification of chromosome regions. Region 17p11.2 approximately p12 is frequently found to be amplified in this tumor, suggesting the presence of an oncogene (or oncogenes) important in osteosarcoma tumorigenesis. We had previously determined amplification profiles for this region. Reasoning that amplification of a causative oncogene in a tumor should result in increased expression of that gene, we have now determined the expression status of genes and expressed sequence tags (ESTs) in 17p11.2 approximately p12. We constructed a 17p11.2 approximately p12-specific macroarray containing 40 genes and 21 ESTs from this region, which was used for expression profiling of 11 osteosarcoma samples (9 tumors and 2 cell lines) and of normal human osteoblasts. Compared to normal osteoblasts, genes with at least threefold increased expression were considered to be overexpressed in the tumor. Genes PMP22 and COPS3, EST AA126939 (encoding part of the hypothetical protein FLJ20343), and two anonymous ESTs (AA918483 and R02360) were found to be most consistently overexpressed after amplification. By real-time reverse transcriptase polymerase chain reaction, we could confirm the overexpression status of PMP22 and COPS3 but not of FLJ20343. We conclude that PMP22 and COPS3, and possibly also the three ESTs, are candidate amplification targets in 17p11.2 approximately p12 in osteosarcoma.

Adult↗
PubMed2006

Jun activation domain-binding protein 1 binds Smad5 and inhibits bone morphogenetic protein signaling.

OBJECTIVE: Bone morphogenetic proteins (BMPs) play an important role in the development and the homeostasis and pathology of cartilage tissue, particularly in the differentiation and anabolic activity of chondrocytes. The present study was undertaken to identify binding partners of the Smad proteins, the intracellular mediators of BMP activity, which might actively modify BMP signaling in chondrocytes. METHODS: Yeast 2-hybrid technology was used to screen a complementary DNA library, constructed from human adult articular cartilage, for molecular binding partners of Smad5, a major intracellular mediator of BMP signaling. Primary interaction partners were verified by coimmunoprecipitation, and the relevance of the interactions to BMP signaling was evaluated by transcriptional reporter assay. Additionally, messenger RNA expression analysis (conventional and quantitative polymerase chain reaction) and immunostaining were performed in adult normal and osteoarthritic articular cartilage. RESULTS: We identified a novel Smad5 interactor, Jun activation domain-binding protein 1 (Jab1), expressed in adult cartilage. The interaction was confirmed in coimmunoprecipitation experiments. Overexpression of Jab1 resulted in an attenuation of BMP-dependent transcriptional responses, suggesting that Jab1 acts as an inhibitor of BMP signaling. CONCLUSION: Jab1 is a newly identified intracellular (negative) modulator of BMP signaling in chondrocytes and other cells. Jab1 represents an interesting molecule for understanding anabolic signaling in chondrocytes, as well as a potential therapeutic target for anabolic activation. Most interestingly, Jab1 appears to crosslink the BMP and interleukin-1 pathways.

Aged↗