Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
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PMID:Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. 946 Dec 17

In vertebrate embryos, signaling via the beta-catenin protein is known to play an essential role in the induction of the dorsal axis. In its signaling capacity, beta-catenin acts directly to affect target gene transcription, in concert with transcription factors of the TCF/LEF family. We have developed a cell-free in vitro assay for beta-catenin signaling activity that utilizes transcriptionally active nuclei and cytoplasm from cleavage-blocked Xenopus laevis embryos. Under these assay conditions, we demonstrate that either addition of beta-catenin protein or upstream activation of the beta-catenin signaling pathway can induce the expression of developmentally relevant target genes. Addition of exogenous beta-catenin protein induced expression of Siamois, XTwin, Xnr3, and Cerberus mRNAs in a protein synthesis independent manner, whereas a panel of other Spemann organizer-specific genes did not respond to beta-catenin. Lithium induction of the beta-catenin signaling pathway, which is thought to cause beta-catenin accumulation by inhibiting its proteasome-dependent degradation, caused increased expression of Siamois in a protein synthesis independent fashion. This result suggests that beta-catenin derived from a preexisting pool can be activated to signal, and that accumulation of this activated form does not require ongoing synthesis. Furthermore, activation of the signaling pathway with lithium did not detectably alter cytoplasmic beta-catenin levels and was insensitive to inhibition of the proteasome- dependent degradation pathway. Taken together, these results suggest that activation of beta-catenin signaling by lithium in this system may occur through a distinct activation mechanism that does not require modulation of levels through regulation of proteasomal degradation.
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PMID:A cell-free assay system for beta-catenin signaling that recapitulates direct inductive events in the early xenopus laevis embryo. 1052 41

Wingless/Wnt signaling directs cell-fate choices during embryonic development. In Drosophila, Wingless signaling mediates endoderm induction and the establishment of segment polarity in the developing embryo. The fly Wingless cascade is strikingly similar to the vertebrate Wnt signaling pathway, which controls a number of key developmental decisions such as dorsal-ventral patterning in Xenopus. Factors of the TCF/LEF HMG domain family (Tcfs) have recently been established as the downstream effectors of the Wingless/Wnt signal transduction pathways. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic beta-catenin (or its fly homolog, Armadillo). There is also a concomitant translocation of beta-catenin/Armadillo to the nucleus, where it interacts with a specific sequence motif at the N terminus of Tcfs to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes including Siamois and Nodal related gene-3 in Xenopus, engrailed and Ultrabithorax in Drosophila via the sequence-specific HMG box, and mediates their transcriptional activation by virtue of transactivation domains contributed by beta-catenin/Armadillo. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3 beta, is activated, which mediates the downregulation of cytoplasmic beta-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear beta-catenin, the Tcfs recruit the corepressor protein Groucho to the target gene enhancers and actively repress their transcription. An additional corepressor protein, CREB-binding protein (CBP), may also be involved in this repression of Tcf target gene activity. Several other proteins, including adenomatous polyposis coli (APC), GSK3 beta, and Axin/Conductin, are instrumental in the regulation of beta-catenin/Armadillo. In APC-deficient colon carcinoma cell lines, beta-catenin accumulates and is constitutively complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/beta-catenin complexes as a result of dominant mutations in the N terminus of beta-catenin that render it insensitive to downregulation by APC, GSK3 beta, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc. Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression as a result of constitutive Tcf-4/beta-catenin activity promotes uncontrolled intestinal cell proliferation. This would readily explain the formation of intestinal polyps during colon carcinogenesis. Similar mechanisms leading to deregulation of Tcf target gene activity are likely to be involved in melanoma and other forms of cancer.
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PMID:The Yin-Yang of TCF/beta-catenin signaling. 1054 54

beta-catenin mediates Wnt signaling by acting as the essential co-activator for TCF transcription factors. Wnt signaling increases the half-life and therefore the absolute level of beta-catenin in responding cells. The current model states that these changes in beta-catenin stability set the threshold for Wnt signaling. However, we find that pharmacological inhibition of proteasome activity by ALLN leads to accumulation of cytosolic beta-catenin but not to increased TCF-mediated transcription. In addition, in temperature-sensitive ubiquitylation mutant CHO cells inhibition of ubiquitylation increases beta-catenin levels, but does not induce transcriptional activation of TCF reporter genes. Using an antibody specific for beta-catenin dephosphorylated at residues Ser37 and Thr41, we show that Wnt signals specifically increase the levels of dephosphorylated beta-catenin, whereas ALLN does not. We conclude that changes in the phosphorylation status of the N-terminus of beta-catenin that occur upon Wnt signaling independently affect the signaling properties and half-life of beta-catenin. Hence, Wnt signals are transduced via N-terminally dephosphorylated beta-catenin.
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PMID:Wnt signals are transmitted through N-terminally dephosphorylated beta-catenin. 1175 73

The Wnt signalling cascade plays an important role during embryonic patterning and cell fate determination and is highly conserved throughout evolution. Factors of the TCF/LEF HMG domain family (Tcfs) are the downstream effectors of this signal transduction pathway. Upon Wnt signalling, a cascade is initiated that results in the translocation of beta-catenin to the nucleus, where it interacts with Tcf to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes. In the absence of Wnt signals, beta-catenin is degraded in the cytoplasm via the ubiquitin-proteasome pathway. Several proteins are instrumental in achieving this tight regulation of beta-catenin levels in the cell, including adenomatous polyposis coli (APC), GSK3 beta, and Axin/Conductin. Deregulation of the Wnt signalling pathway is implicated in several forms of cancer, such as colon carcinoma and melanoma. This deregulation is achieved via mutation of APC, beta-catenin or Axin, resulting in elevated beta-catenin levels and the presence of constitutively active Tcf-beta-catenin complexes in the nucleus. The accompanying inappropriate activation of target genes is considered to be a critical, early event in this carcinogenesis. In addition to regulating beta-catenin levels, normal healthy cells have evolved a second level of regulation, by manipulating the activity of the Tcf proteins themselves. In the absence of Wnt signalling, Tcf complexes with several transcriptional repressor proteins ensuring active repression of Tcf target genes. In this review the dual role of Tcf proteins in the Wnt signalling cascade will be discussed.
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PMID:TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. 1193 63

beta-Catenin is a key player in the Wnt signaling pathway, and interacts with cofactor T cell factor/lymphoid enhancer factor (TCF/LEF) to generate a transcription activator complex that activates Wnt-induced genes. We previously reported that Nemo-like kinase (NLK) negatively regulates Wnt signaling via phosphorylation of TCF/LEF. To further evaluate the physiological roles of NLK, we performed yeast two-hybrid screening to identify NLK-interacting proteins. From this screen, we isolated a novel RING finger protein that we term NARF (NLK associated RING finger protein). Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. Furthermore, NARF inhibited formation of the secondary axis induced by the ectopic expression of beta-catenin in Xenopus embryos. Collectively, our findings raise the possibility that NARF functions as a novel ubiquitin-ligase to suppress the Wnt-beta-catenin signaling.
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PMID:NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). 1671 85

The beta-catenin signaling pathway is dysregulated in most cases of colon cancer resulting in an accumulation of nuclear beta-catenin and increased transcription of genes involved in tumor progression. This study examines the effect of retinol on beta-catenin protein levels in three all-trans retinoic acid (ATRA)-resistant human colon cancer cell lines: HCT-116, WiDr, and SW620. Each cell line was treated with increasing concentrations of retinol for 24 or 48 h. Retinol reduced beta-catenin protein levels and increased ubiquitinated beta-catenin in all cell lines. Treatment with the proteasomal inhibitor MG132 blocked the retinol-induced decrease in beta-catenin indicating retinol decreases beta-catenin by increasing proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah-1/adenomatous polyposis coli (APC), a Wnt/glycogen synthase kinase-3beta/APC, and a retinoid "X" receptor (RXR)-mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr), only the RXR-mediated pathway remains functional in each cell line. To determine if RXRs facilitate beta-catenin degradation, cells were treated with the RXR pan-antagonist, PA452, or transfected with RXRalpha small interfering RNA (siRNA). The RXR pan-antagonist and RXRalpha siRNA reduced the ability of retinol to decrease beta-catenin protein levels. Nuclear beta-catenin induces gene transcription via interaction with T cell factor/lymphoid enhancer factor (TCF/LEF) proteins. Retinol treatment decreased the transcription of a TOPFlash reporter construct and mRNA levels of the endogenous beta-catenin target genes, cyclin D1 and c-myc. These results indicate that retinol may reduce colon cancer cell growth by increasing the proteasomal degradation of beta-catenin via a mechanism potentially involving RXR.
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PMID:Retinol decreases beta-catenin protein levels in retinoic acid-resistant colon cancer cell lines. 1721 22

Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4alpha (HNF4alpha). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4alpha and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4alpha (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4alpha as well as decreased endogenous HNF4alpha protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor alpha, retinoid X receptor alpha, and thyroid hormone receptor beta) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor alpha and peroxisome proliferator-activated receptor alpha. Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs.
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PMID:Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization. 1738 49

Multiple myeloma (MM) is an invariably fatal form of cancer characterized by clonal proliferation of malignant plasma cells in the bone marrow. The canonical Wnt signaling pathway is activated in MM cells through constitutively active beta-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. The identification of a number of small molecular compounds, such as PKF115-584, which disrupt the interaction of the transcriptionally active beta-catenin/TCF protein complex, provides valuable new therapeutic tools to target an alternative pathway in MM independent of the proteasome. Here we evaluated the transcriptional, proteomic, signaling changes, and biological sequelae associated with the inhibition of Wnt signaling in MM by PKF115-584. The compound blocks expression of Wnt target genes and induces cytotoxicity in both patient MM cells and MM cell lines without a significant effect in normal plasma cells. In xenograft models of human MM, PKF115-584 inhibits tumor growth and prolongs survival. Taken together, these data demonstrate the efficacy of disrupting the beta-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM.
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PMID:Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. 1745 41

Beta-catenin is the central signalling molecule of the canonical Wnt pathway, where it activates target genes in a complex with lymphoid enhancer factor/T-cell factor transcription factors in the nucleus. The regulation of beta-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3beta (GSK-3beta) that phosphorylates beta-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3beta has a nuclear function in downregulating the activity of beta-catenin. Using colorectal cell lines that express a mutant form of beta-catenin, which cannot be phosphorylated by GSK-3beta and ectopically expressed mutant beta-catenin protein, we show that nuclear GSK-3beta functions in a mechanism that does not involve beta-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3beta enters the nucleus, forms a complex with beta-catenin and lowers the levels of beta-catenin/TCF-dependent transcription in a mechanism that involves GSK-3beta-Axin binding.
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PMID:Nuclear GSK-3beta inhibits the canonical Wnt signalling pathway in a beta-catenin phosphorylation-independent manner. 1822 84


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