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)

The proteasome is a large multiprotein complex that processes intracellular proteins functioning as cell cycle regulators and transcription factors. It has been shown that the chymotryptic component of the proteasome is an important regulator of osteoblast differentiation and bone formation, with inhibitors of the proteasome increasing osteoblast differentiation and bone formation. Yet, little is known about the effects of the proteasomal activity in the growth plate. In the present study, we cultured rat metatarsal bones in the presence of proteasome inhibitor I (PSI), a known inhibitor of the chymotrypsin-like activity of the 20S proteasome. PSI suppressed growth plate chondrocyte proliferation and hypertrophy/differentiation, and induced chondrocyte apoptosis. All these cellular effects led to reduced metatarsal linear growth. In cultured chondrocytes, PSI increased the expression of beta-catenin (a negative regulator of chondrogenesis) and reduced the DNA binding of nuclear factor kappaB, a transcription factor that stimulates growth plate chondrogenesis. In conclusion, our findings suggest that the proteasomal activity facilitates growth plate chondrogenesis and, in turn, longitudinal bone growth.
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PMID:Inhibition of the proteasomal function in chondrocytes down-regulates growth plate chondrogenesis and longitudinal bone growth. 1667 23

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

Studies have demonstrated cross talk between beta-catenin and peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathways. Specifically, activation of PPARgamma induces the proteasomal degradation of beta-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic beta-catenin is resistant to such degradation and inhibits the expression of PPARgamma target genes. In the present studies, we demonstrate a functional interaction between beta-catenin and PPARgamma that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of beta-catenin and a catenin binding domain (CBD) within PPARgamma. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic beta-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPARgamma. Furthermore, these mutations render S37A beta-catenin susceptible to proteasomal degradation in response to activation of PPARgamma. Mutation of F372 within the CBD (helices 7 and 8) of PPARgamma disrupts its binding to beta-catenin and significantly reduces the ability of PPARgamma to induce the proteasomal degradation of beta-catenin. We suggest that in normal cells, PPARgamma can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated beta-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain.
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PMID:Functional interaction between peroxisome proliferator-activated receptor gamma and beta-catenin. 1684 34

In cultured bovine adrenal chromaffin cells, 12-h treatment with 1-20 mM LiCl, an inhibitor of glycogen synthase kinase-3 (GSK-3), increased Ser(9) phosphorylation of GSK-3beta by approximately 44%, while decreasing insulin receptor substrate-1 (IRS-1) and IRS-2 protein levels by approximately 38 and approximately 62% in a concentration-dependent manner. Treatment with SB216763 (0.1-30 microM for 12 h), a selective inhibitor of GSK-3, lowered IRS-1 and IRS-2 levels by approximately 38 and approximately 48%, while increasing beta-catenin protein level by approximately 47%, due to the prevention of GSK-3-induced degradation of beta-catenin by SB216763. Insulin (100 nM for 24 h) increased Ser(9) phosphorylation of GSK-3beta by approximately 104%, while decreasing IRS-1 and IRS-2 levels by approximately 41 and approximately 72%; the insulin-induced Ser(9) phosphorylation of GSK-3beta, as well as down-regulations of IRS-1 and IRS-2 levels were restored to the control levels of nontreated cells at 24 h after the washout of the insulin (100 nM for 12 h)-treated cells. Either clasto-lactacystin beta-lactone or lactacystin (an inhibitor of proteasome) prevented LiCl- or SB216763-induced decreases of IRS-1 and IRS-2 levels by approximately 100 and approximately 69%, respectively. In contrast, calpastatin (an inhibitor of calpain) and leupeptin (an inhibitor of lysosome) failed to prevent the decreases of IRS-1 and IRS-2 levels caused by LiCl or SB216763. LiCl or SB216763 lowered IRS-2 mRNA level, with no effect on IRS-1 mRNA level. These results suggest that constitutive activity of GSK-3beta in quiescent cells positively maintains steady-state levels of IRS-1 and IRS-2 via regulating proteasomal degradation and/or synthesis of IRS-1 and IRS-2 proteins.
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PMID:Constitutive activity of glycogen synthase kinase-3beta: positive regulation of steady-state levels of insulin receptor substrates-1 and -2 in adrenal chromaffin cells. 1687 Jan 61

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/beta-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.
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PMID:Emerging drugs for hepatocellular carcinoma. 1693 86

Inhibitors of histone deacetylases (HDAC) inhibit malignant cell growth and induce apoptosis through unknown mechanisms. Here, we report that the expression status of adenomatous polyposis coli (APC) protein determines the relative sensitivity of colon cancer cells to HDAC inhibitor-induced apoptosis. HCA-7 cells (expressing wild-type beta-catenin and APC proteins) are more sensitive to apoptosis induced by HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid than SW620 or HT-29 cells (both expressing mutant APC). When wild-type APC protein was expressed using an inducible expression system, HT-29 cells became sensitive to apoptosis in response to VPA. Conversely, knocking down of endogenous APC protein by small interfering RNA (siRNA) blocked VPA-induced apoptosis in HCA-7 cells. APC mediated VPA-induced apoptosis through down-regulation of survivin. The level of survivin protein decreased in HCA-7 and HT-29/APC cells, but not in SW620 and HT-29/beta-Gal cells after VPA treatment. Whereas knocking down of survivin by siRNA sensitized SW620 cells to VPA-induced apoptosis, overexpression of survivin blocked VPA-induced apoptosis in HCA-7 cells. Down-regulation of survivin transcription occurred through changes in GSK-3beta/beta-catenin/Tcf-4 signaling molecules. VPA also induced proteasome-mediated degradation of survivin protein in HCA-7 cells. Furthermore, we have shown that APC mutation-mediated resistance to apoptosis can be overcome by cotreatment with Flavopiridol, which promotes survivin degradation. These results suggest that APC is a critical determinant of HDAC inhibitor-induced apoptosis in colon cancer cells and survivin is a potential target to enhance apoptotic response to HDAC inhibitors.
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PMID:Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells. 1698 69

Mutations in the human adenomatous polyposis coli (APC) gene are thought to initiate colorectal tumorigenesis. The tumor suppressor function of APC is attributed primarily to its ability to regulate the WNT pathway by targeting the destruction of beta-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminal-binding protein-1 (CtBP1) through a proteasome-dependent process. Further, CtBP1 suppresses the expression of intestinal retinol dehydrogenases, which are required for retinoic acid production and intestinal differentiation. In support of a role for CtBP1 in initiation of colorectal cancer, adenomas taken from individuals with familial adenomatous polyposis contain high levels of CtBP1 protein in comparison with matched, uninvolved tissue. The relationship between APC and CtBP1 is conserved between humans and zebrafish and provides a mechanistic model explaining APC control of intestinal retinoic acid biosynthesis.
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PMID:Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases. 1702 96

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

NDRG1 is known to play important roles in both androgen-induced cell differentiation and inhibition of prostate cancer metastasis. However, the proteins associated with NDRG1 function are not fully enumerated. Using coimmunoprecipitation and mass spectrometry analysis, we identified 58 proteins that interact with NDRG1 in prostate cancer cells. These proteins include nuclear proteins, adhesion molecules, endoplasmic reticulum (ER) chaperons, proteasome subunits, and signaling proteins. Integration of our data with protein-protein interaction data from the Human Proteome Reference Database allowed us to build a comprehensive interactome map of NDRG1. This interactome map consists of several modules such as a nuclear module and a cell membrane module; these modules explain the reported versatile functions of NDRG1. We also determined that serine 330 and threonine 366 of NDRG1 were phosphorylated and demonstrated that the phosphorylation of NDRG1 was prominently mediated by protein kinase A (PKA). Further, we showed that NDRG1 directly binds to beta-catenin and E-cadherin. However, the phosphorylation of NDRG1 did not interrupt the binding of NDRG1 to E-cadherin and beta-catenin. Finally, we showed that the inhibition of NDRG1 expression by RNA interference decreased the ER inducible chaperon GRP94 expression, directly proving that NDRG1 is involved in the ER stress response. Intriguingly, we observed that many members of the NDRG1 interactome are androgen-regulated and that the NDRG1 interactome links to the androgen response network through common interactions with beta-catenin and heat shock protein 90. Therefore we overlaid the transcriptomic expression changes in the NDRG1 interactome in response to androgen treatment and built a dual dynamic picture of the NDRG1 interactome in response to androgen. This interactome map provides the first road map for understanding the functions of NDRG1 in cells and its roles in human diseases, such as prostate cancer, which can progress from androgen-dependent curable stages to androgen-independent incurable stages.
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PMID:Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgen response program in prostate cancer cells. 1722 Apr 78

Siah-1 (seven in absentia homolog) is known to cause indirect degradation of beta-catenin through formation of a complex with Siah-interacting protein (SIP), Skp1 and Ebi. Here, we report the characterization of a novel splice variant of human Siah-1, designated Siah-1S, which is produced by an alternative splicing mechanism. The novel intron/exon junctions used to generate Siah-1S follow a non-conventional CT-AC rule. Siah-1S exhibits an even shorter half-life than Siah-1 and is able to catalyse self-ubiquitination that results in its subsequent degradation by proteasome. Siah-1S is shown to upregulate beta-catenin-dependent Tcf/Lef transcriptional activation and antagonize Siah-1's potentiation effect on the apoptosis induced by etoposide in MCF-7 cells. Additionally, Siah-1S is found to interact with Siah-1 to form heterodimer or with itself to form homodimer. Unlike homodimer Siah-1*Siah-1, neither Siah-1*Siah-1S nor Siah-1S*Siah-1S is able to bind to Siah-1-interacting protein, which may explain the underlying mechanism for Siah-1S's dominant negative effect on Siah-1. Importantly, results from in vitro soft agar assay demonstrated that Siah-1S displays a promotion effect on cells tumorigenicity.
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PMID:Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of beta-catenin. 1742 Jul 21


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