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 dioxin receptor (AhR), in addition to its role in xenobiotic-induced carcinogenesis, appears to participate in cell proliferation, differentiation and organ homeostasis. Understanding potential mechanisms of activation of this receptor in the absence of exogenous ligands is therefore important to study its contribution to endogenous cellular functions. Using mouse embryo primary fibroblasts, we have previously shown that proteasome inhibition increased AhR transcriptional activity in the absence of xenobiotics. We suggested that proteasome inhibition-dependent AhR activation could involve an increase in the expression of the partner protein dioxin receptor nuclear translocator (ARNT). Since ARNT over-expression induced nuclear translocation of the AhR, and ARNT-deficient cells were unable to translocate this receptor to the nucleus upon proteasome inhibition, we have analyzed the effect of proteasome inhibition on the expression of regulatory proteins controlling ARNT levels. Treatment with the proteasome inhibitor MG132 increased endogenous Sp1 phosphorylation and its DNA-binding activity to the ARNT promoter. Sp1 phosphorylation and binding to the ARNT promoter, ARNT over-expression and AhR nuclear translocation were inhibited by GF109203X, a protein kinase C-specific inhibitor. In addition, MG132 stimulated protein kinase C activity in MEF cells with a pattern similar to that observed for ARNT expression. These data suggest that cellular control of protein kinase C activity, through Sp1 and ARNT, could regulate AhR transcriptional activity in the absence of xenobiotics.
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PMID:Proteasome inhibition induces nuclear translocation of the dioxin receptor through an Sp1 and protein kinase C-dependent pathway. 1452 14

Cellular proteins are degraded within two distinct compartments: the proteasome and the lysosome. Alterations in proteasomal degradation can contribute to carcinogenesis. In contrast, alterations in autophagic protein degradation through the lysosome have not been linked to cancer. Now two reports demonstrate that the autophagic gene, Beclin 1, is a haploinsufficient tumor suppressor gene. These new data suggest that autophagic degradation provides an important mechanism to prevent cellular transformation.
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PMID:Defective autophagy leads to cancer. 1470 33

Several effects of bile acids (BAs) on colonic epithelial cells (CECs) have been described, including induction of proliferation and apoptosis. Some of these effects are mediated through activation of the NF-kappa B transcriptional system. In this study, we investigated the molecular mechanisms underlying the BA-induced gene expression in CECs. The human CEC line HT-29 and primary human CECs were treated with dilutions of salts of deoxycholic acid (DCA) and taurodeoxycholic acid (TDCA). NF-kappa B binding activity was analyzed with EMSA, RelA translocation with immunofluorescence, and I kappa B alpha- and RelA-phosphorylation with Western blot analysis. IL-8 mRNA and protein expression were assessed by quantitative PCR and ELISA. Functional impact of NF-kappa B activation was determined by blocking the proteasome activity with MG132 or by preventing IKK activity with a dominant-negative IKK beta delivered by adenoviral dominant-negative (dn) IKK beta (Ad5dnIKK beta). DCA and TDCA induced IL-8 expression in a dose- and time-dependent manner. It is interesting that DCA but not TDCA induced I kappa B alpha-phosphorylation, RelA translocation, and NF-kappa B binding activity. Accordingly, the proteasome inhibitor MG132 blocked DCA- but not TDCA-induced IL-8 gene expression. In contrast, TDCA-induced IL-8 gene expression correlated with enhanced RelA phosphorylation, which was blocked by Ad5dnIKK beta. Our data suggest that DCA-induced signal transduction mainly utilized the I kappa B degradation and RelA nuclear translocation pathway, whereas TDCA primarily induced IL-8 gene expression through RelA phosphorylation. These differences may have implications for the understanding of the pathophysiology of inflammation and carcinogenesis in the gut.
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PMID:Differential effects of deoxycholic acid and taurodeoxycholic acid on NF-kappa B signal transduction and IL-8 gene expression in colonic epithelial cells. 1472 7

The adhesion receptor SHPS-1 activates the protein-tyrosine-phosphatase SHP-2 and thereby promotes integrin-mediated reorganization of the cytoskeleton. SHPS-1 also contributes to cell-cell communication through association with CD47. Although functional alteration of SHPS-1 is implicated in cellular transformation, the role of the CD47-SHPS-1 interaction in carcinogenesis has been unclear. A soluble SHPS-1 ligand (CD47-Fc) has now been shown to bind to Melan-a non-tumorigenic melanocytes but not to syngeneic B16F10 melanoma cells. Treatment of B16F10 cells with 1-deoxymannojirimycin, which prevents N-glycan processing, restored the ability of SHPS-1 derived from these cells to bind CD47-Fc in vitro, indicating that aberrant N-glycosylation of SHPS-1 impairs CD47 binding in B16F10 cells. CD47-Fc inhibited the migration of Melan-a cells but not that of B16F10 cells. However, a monoclonal antibody that reacts with SHPS-1 on both Melan-a and B16F10 cells inhibited the migration of both cell types similarly. CD47 binding induced proteasome-mediated degradation of SHPS-1 in a tyrosine phosphorylation-independent manner. Furthermore, overexpression of SHPS-1 reduced the level of tyrosine phosphorylation of focal adhesion kinase, and this effect was reversed by CD47 binding. These results suggest that CD47 binds to and thereby down-regulates SHPS-1 on adjacent cells, resulting in inhibition of cell motility. Resistance to this inhibitory mechanism may contribute to the highly metastatic potential of B16 melanoma.
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PMID:Resistance of B16 melanoma cells to CD47-induced negative regulation of motility as a result of aberrant N-glycosylation of SHPS-1. 1473 97

The regulation of protein stability by the ubiquitin-proteasome pathway is a critical issue central to the comprehension of the molecular basis of carcinogenesis. However, ubiquitin modification of target substrates signals many cellular processes other than proteolysis that are also important for the development of cancer. It is noteworthy that many proteins studied by clinical breast cancer researchers are involved in these ubiquitin pathways. This review summarizes recent works on such proteins including cyclins, CDK inhibitors, and the SCF in cell cycle control; the breast and ovarian cancer suppressor BRCA1-BARD1; ErbB2/HER2/Neu and its ubiquitin ligase c-Cbl or CHIP; and the estrogen receptor and its downstream target Efp. Understanding these pathways may provide some hints toward developing diagnostic tools and treatments for breast cancer patients.
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PMID:Ubiquitin and breast cancer. 1502 95

FUS1 is a novel tumor suppressor gene identified in the human chromosome 3p21.3 region that is deleted in many cancers. Using surface-enhanced laser desorption/ionization mass spectrometric analysis on an anti-Fus1-antibody-capture ProteinChip array, we identified wild-type Fus1 as an N-myristoylated protein. N-myristoylation is a protein modification process in which a 14-carbon myristoyl group is cotranslationally and covalently added to the NH2-terminal glycine residue of the nascent polypeptide. Loss of expression or a defect of myristoylation of the Fus1 protein was observed in human primary lung cancer and cancer cell lines. A myristoylation-deficient mutant of the Fus1 protein abrogated its ability to inhibit tumor cell-induced clonogenicity in vitro, to induce apoptosis in lung tumor cells, and to suppress the growth of tumor xenografts and lung metastases in vivo and rendered it susceptible to rapid proteasome-dependent degradation. Our results show that myristoylation is required for Fus1-mediated tumor-suppressing activity and suggest a novel mechanism for the inactivation of tumor suppressors in lung cancer and a role for deficient posttranslational modification in tumor suppressor-gene-mediated carcinogenesis.
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PMID:Myristoylation of the fus1 protein is required for tumor suppression in human lung cancer cells. 1512 27

Human papillomaviruses (HPVs) are aetiological agents for genital warts and cervical cancer, the different pathologies of which are dependent on the type of HPV infection. Oncogenic HPV types associated with cancer are carcinogens by virtue of their oncogene products, which target key regulators of cell proliferation and apoptosis. The viral E6 protein from oncogenic HPV types plays a central role in carcinogenesis by exploiting the cellular proteasome degradation pathway in order to mediate the degradation of cellular proteins, most notably the prototype tumour suppressor protein p53. Much less is known about the cellular targets of E6 from the non-oncogenic HPV types associated with genital warts. It is also unclear what factors influence the level and stability of the viral E6 proteins in cells. This report demonstrates that both oncogenic and non-oncogenic HPV E6 proteins (from types 18 and 11, respectively) are ubiquitinated and targeted for degradation by the 26S proteasome. E6 domains required for the induction of p53 or DLG degradation, or E6AP binding, are not involved in proteasome-mediated degradation of HPV-18 E6. These results provide insight into the cellular modulation of E6 protein levels from both high-risk and low-risk HPV types.
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PMID:Ubiquitination and proteasome degradation of the E6 proteins of human papillomavirus types 11 and 18. 1516 24

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either TSC1 or TSC2 tumor suppressor gene. TSC1 and TSC2 products, Harmatin and Tuberin, form the functional complex to serve as the negative regulator for insulin-induced phosphorylation of S6 kinase and elF4E-binding protein 1. High-risk human papillomavirus (HPV) infection is the necessary cause for cervical cancer. E6 oncoprotein encoded by HPV plays a pivotal role in carcinogenesis by interference with the host intracellular protein functions. In this study, we show that HPV16 E6 interacts with tumor suppressor gene TSC2 product, Tuberin, and results in the phosphorylation of S6 kinase and S6 even in the absence of insulin. The overexpression of Tuberin overcomes the effect of E6 on S6 kinase phosphorylation. Binding with HPV16 E6 causes the proteasome-mediated degradation of Tuberin. A DILG motif and an ELVG motif located in the carboxyl-terminal of Tuberin are required for E6 binding. In addition, the Tuberin interaction region in E6 has been mapped in the amino-terminal portion of HPV16 E6, which is different from the binding domain with p53. These results provide a possible link between E6-induced oncogenesis and the insulin-stimulated cell proliferation signaling pathway.
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PMID:Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin. 1517 23

Controlled intracellular protein degradation is crucial for the maintenance of normal cell functions. An evolving concept claims that alterations in the exact timely degradation of proteins involved in growth control, apoptosis, signaling and differentiation contribute to carcinogenesis. This tightly regulated process is facilitated by the ubiquitin-26S proteasome system, a multi-enzyme complex, and inhibitors of this pathway have already been developed as potential anticancer agents. In order to generate proteasomal protein expression patterns of tumor cells and to provide an analytical tool we applied two-dimensional electrophoresis (2-DE) followed by mass spectrometry (MALDI-TOF-TOF with LIFT technology) in ten individual tumor cell lines (Saos-2; SK-N-SH; HCT-116; Caov3; A-549; HL60; A-673; A-375; MCF-7; HeLa) widely used in tumor research. A series of 39 proteasomal/proteolytic proteins was unambiguously identified by this proteomic approach, comprising proteins of the 20S core complex, the 19S regulatory complex, the 11S regulator, components of the ubiquitin pathway and proteases. Construction of individual protein maps by 2-DE and mass spectrometry provides an analytical tool and reference base for studying the pivotal importance of the proteasome and other proteolytic enzymes in tumor cells, independent of antibody availability and specificity. This preliminary database enables for designing studies in this area of research and reveals proteins that can be used as targets for new therapeutic strategies.
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PMID:Expression of proteasomal proteins in ten different tumor cell lines. 1545 11

Expression of cyclin E is believed to be a critical factor promoting cell entry into the S-phase and cell proliferation. Indeed, normal proliferating cells and most tumor cell lines are characterized by the existence of a minimal cyclin E threshold level in the G1-phase, and only those cells expressing cyclin E over this threshold enter into the S-phase of the cell cycle. However, through studying clinical tumor tissue specimens, we recently observed that some cancer cells can enter into the S-phase with minimal levels of cyclin E expression. In an effort to establish an in vitro cell model system for studying the mechanisms underlying this phenomenon, we treated MOLT-4 lymphocyte leukemia cells with 50 mM caffeine and found that the levels of cyclin E expression were decreased markedly in these cells following 2 to 4-h exposure to caffeine. Quite unexpectedly, we observed that the percentage of the cells progressing through the S-phase increased despite the reduced levels of cyclin E, as analyzed for the cellular DNA contents, expression of nuclear-bound PCNA, immunolabelling with Ki-67 antibody and incorporation of BrdU. In fact, these cells entered into the S-phase with a level of cyclin E well below the threshold level for untreated cells, thus suggesting that lower levels of cyclin E expression are associated with cell proliferation under certain circumstances. We speculate that caffeine may enhance MOLT-4 cell entrance into the S-phase through activation of Cdc25, which in turn activates cyclin-dependent protein kinases (CDKs) including CDK2 and drives the cell cycle progression; while degradation of cyclin E by the ubiquitin/proteasome pathway may account for the decreased levels of cyclin E in these cells. Our findings from both the MOLT-4 cell line and patients' cancer tissues may help decipher the mystery of the deregulation of cell cycle progression and carcinogenesis in some malignant tumors.
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PMID:Down-regulation of cyclin E expression by caffeine promotes cancer cell entry into the S-phase of the cell cycle. 1551 6


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