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)

Inactivation of the tumor suppressor protein p53 plays a key role in human carcinogenesis. Activation of the growth-suppressive properties of p53 by appropriate stress signals, including genotoxic stress, is generally accompanied by intracellular accumulation of the protein. This suggests that stabilization of the otherwise short-lived protein is an intrinsic feature of p53 activation. The ubiquitin/proteasome system is believed to be a major proteolytic system involved in selective degradation of cell regulatory proteins. In this review, the potential role of the ubiquitin/proteasome system in p53 degradation and possible mechanisms involved in p53 stability regulation are discussed.
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PMID:Ubiquitin, E6-AP, and their role in p53 inactivation. 969 Aug 14

Expression of HPV16 early region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid tumors, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-4 (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.
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PMID:Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. 1036 56

The cyclin-dependent kinase inhibitor p27Kip1 is a negative regulator of cell proliferation. Its expression is known to be altered in a proteasome-dependent manner without changes in DNA level. Reduced expression of p27Kip1 is associated with aggressive behavior in a variety of human cancers. We investigated expression of p27Kip1 protein in human breast cancer using immunohistochemistry to assess its biologic implication along with cell-cycle analysis by flow cytometry. A total of 68 patients with invasive ductal cancer received adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-FU every 3 weeks for six cycles. In epithelial cells of normal and benign breast disease, expression of p27Kip1 was well preserved while its expression markedly decreased in breast cancer (45 of 68). Expression of p27Kip1 is significantly reduced in poorly differentiated cancers and in the advanced stage of the disease. Levels of p27Kip1 expression correlated with cell populations in G0/G1 phase of the cell cycle. In survival analysis, p27Kip1 was useful to predict disease free survival but not overall survival of the patients after adjuvant chemotherapy. In summary, p27Kip1 seems to have a role in the cell proliferation and differentiation process during carcinogenesis of breast cancer. The results of the present study suggest that p27Kip1 can be used in predicting response to systemic chemotherapy in a subset of patients with breast cancer.
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PMID:Reduced expression of p27Kip1 protein is associated with poor clinical outcome of breast cancer patients treated with systemic chemotherapy and is linked to cell proliferation and differentiation. 1048 43

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

Oltipraz (OPZ) is a potent chemopreventive agent against chemically-induced carcinogenesis in several animal models. It affects the expression and/or activity of xenobiotic-metabolizing enzymes and its effects are altered in the course of inflammation in liver. The present study was undertaken to analyse the effect of OPZ alone or in combination with Escherichia coli lipopolysaccharide (LPS) on the expression and activities of glutathione S-transferases (GSTs) and cytochrome P450 (CYPs) in rat lung and kidney. Male Wistar rats were fed a diet containing OPZ for 1-5 days. LPS was injected 24 h before the end of OPZ treatment (from 48 to 72 h). Total GST activity, measured using 1-chloro-2,4-dinitrobenzene as a substrate, increased slightly in both lung and kidney during OPZ treatment. As previously demonstrated in the liver, OPZ induced rat GSTP1 in both kidney and lung and this effect was totally (kidney) or partially (lung) inhibited by co-treatment with LPS. CYP1A expression and activity were strongly increased in both tissues 24 h after starting OPZ treatment and maintained for 5 days. This increase was suppressed during the acute-phase response to endotoxin. OPZ has no effect on CYP2B1 mRNA expression in the lung, but it dramatically decreased the amount and activity of the corresponding apoprotein. The OPZ-dependent decrease in the CYP2B1 apoprotein was abolished and its corresponding activity partially reversed during LPS treatment. In reconstitution experiments using cytosol from OPZ-treated or control rat lungs and microsomal fractions, CYP2B1 apoprotein was rapidly degraded in the presence of cytosol from treated rats. This effect was partially reversed in the presence of MG132, a proteasome inhibitor. These observations support the conclusion that the decrease of CYP2B1 by OPZ involves proteasome-dependent degradation and represents a new mechanism of regulation by this compound.
Carcinogenesis 2001 Jan
PMID:Differential effects of oltipraz on CYP1A and CYP2B in rat lung. 1115 40

DNA topoisomerases are double-edged swords. They are essential for many vital functions of DNA during normal cell growth. However, they are also highly vulnerable under various physiological and nonphysiological stresses because of their delicate act on breaking and rejoining DNA. These stresses (e.g. exposure to topoisomerase poisons, acidic pH, and oxidative stresses) can convert DNA topoisomerases into DNA-breaking nucleases, resulting in cell death and/or genomic instability. The importance of topoisomerase-mediated DNA cleavage in tumor cell death and carcinogenesis has been recognized. This review focuses on recent findings concerning the molecular mechanisms of the stress responses to topoisomerase-mediated DNA damage. The involvement of ubiquitin/26S proteasome and SUMO/UBC9 in these processes, as well as the role of topoisomerase cleavable complexes in apoptotic cell death are discussed.
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PMID:Tumor cell death induced by topoisomerase-targeting drugs. 1126 50

Cellular dedifferentiation is the major process underlying totipotency, regeneration, and formation of new stem cell lineages in multicellular organisms. In animals it is often associated with carcinogenesis. Here, we used tobacco protoplasts (plant cells devoid of cell wall) to study changes in chromatin structure in the course of dedifferentiation of mesophyll cells. Using flow cytometry and micrococcal nuclease analyses, we identified two phases of chromatin decondensation prior to entry of cells into S phase. The first phase takes place in the course of protoplast isolation, following treatment with cell wall degrading enzymes, whereas the second occurs only after protoplasts are induced with phytohormones to re-enter the cell cycle. In the absence of hormonal application, protoplasts undergo cycles of chromatin condensation/decondensation and die. The ubiquitin proteolytic system was found indispensable for protoplast progression into S phase, being required for the second but not the first phase of chromatin decondensation. The emerging model suggests that cellular dedifferentiation proceeds by two functionally distinct phases of chromatin decondensation: the first is a transitory phase that confers competence for cell fate switch, which is followed, under appropriate conditions, by a second proteasome-dependent phase representing a commitment for the mitotic cycle. These findings might have implications for a wide range of dedifferentiation-driven cellular processes in higher eukaryotes.
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PMID:Two phases of chromatin decondensation during dedifferentiation of plant cells: distinction between competence for cell fate switch and a commitment for S phase. 1127 91

In this study, we focus on different modes of regulation of STRA13, a human ortholog of the mouse basic helix-loop-helix transcriptional factor, previously identified by us as a new von Hippel-Lindau tumor suppressor gene (VHL) target. The gene was overexpressed in VHL-deficient cell lines and tumors, specifically clear cell renal carcinomas and hemangioblastomas. Introduction of wild type VHL transgene into clear cell renal carcinoma restored low level expression of STRA13. Overexpression was also detected in many common malignancies with an intact VHL gene, suggesting the existence of another, VHL-independent pathway of STRA13 regulation. Similar to many other von Hippel-Lindau tumor-suppressor protein (pVHL) targets, the expression of STRA13 on the mRNA level was hypoxia-sensitive, indicating oxygen-dependent regulation of the gene, presumably through the pVHL/hypoxia-inducible factor 1 (HIF-1) pathway. The yeast two-hybrid screening revealed interaction of the STRA13 protein with the human ubiquitin-conjugating enzyme (UBC9) protein, the specificity of which was confirmed in mammalian cells. By adding the proteasome inhibitor acetyl-leucinyl-leucinyl-norleucinal, we demonstrated that the 26 S proteasome pathway regulates the stability of pSTRA13. Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. Hypoxia treatment of mammalian cells transiently expressing STRA13 protein showed that stability of pSTRA13 is not affected by hypoxia or VHL. Thus, STRA13, a new pVHL target, is regulated in cells on multiple levels. We propose that STRA13 may play a critical role in carcinogenesis, since it is a potent transcriptional regulator, abundant in a variety of common tumors.
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PMID:Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, hypoxia, and the UBC9/ubiquitin proteasome degradation pathway. 1127 94

Bile acids, principally deoxycholic acid (DCA), have been implicated in the promotion of colon tumorigenesis in both animals and humans. Increasing evidence suggests that bile acids may exert their tumor promoting activity by modulating intracellular signaling and altering gene expression. In this study we have investigated the effect of bile acids on the tumor suppressor p53 using the human colon tumor cell line HCT116, which retains the wild-type p53 gene and functional p53 signaling in response to DNA damage. We found that exposure of the cells to elevated concentrations of DCA suppressed accumulation of p53 protein as well as p53 transactivation and impaired the p53 response of the cells to DNA damaging agents, such as ionizing radiation. Neither ursodeoxycholic acid, a putative chemopreventive agent, nor cholic acid, which is biologically inert, had any effect on p53 protein level and transactivation activity. Further examination revealed that instead of inhibition, DCA induced p53 mRNA in a dose-dependent manner, indicating that the inhibitory effect of DCA on p53 protein is mediated by a post-transcriptional mechanism. Both lactacystin, a specific inhibitor of the 26S proteasome, and leptomycin B, a specific inhibitor of the nuclear export protein CRM1, could block the effect that DCA had on p53 protein levels, suggesting that DCA suppressed p53 by stimulating the process of proteasome-mediated degradation of p53. Significantly, blocking extracellular signal-regulated kinase (ERK) signaling, but not protein kinase C (PKC), blunted suppression by DCA of p53 protein levels and transactivation activity, suggesting that DCA suppressed p53, in part, by stimulating the ERK signaling pathway. Both ERK and PKC signaling have been previously demonstrated to be stimulated by DCA. These results suggest a novel signaling mechanism of bile acids that may play an important role in colon tumor promotion mediated by bile acids.
Carcinogenesis 2001 Jun
PMID:Deoxycholic acid suppresses p53 by stimulating proteasome-mediated p53 protein degradation. 1137 5

The CYP1A1 gene encodes microsomal cytochrome P4501A1 that catalyzes the metabolism of many xenobiotics, including the oxygenation of polycyclic aromatic hydrocarbons (PAH). Induction of CYP1A1 enhances the metabolism of PAHs, and therefore, represents an adaptive response to chemical exposure in mammalian cells. Mechanistic studies reveal an AhR/DRE paradigm for the induction, which involves activation of the aryl hydrocarbon receptor (AhR) by an agonist, dimerization of AhR with the Ah recceptor nuclear translocator (Arnt), followed by binding of the AhR/Arnt heterodimer to the dioxin-responsive enhancer (DRE) and transcription of the gene. The AhR mediated transcription is tightly regulated through, at least, two mechanisms: (a) the cytoplasmic AhR interacts with hsp90 and an immunophilin chaperone AIP for proper folding and receptivity, and (b) the agonist-activated, nuclear AhR is degraded through the ubiquitin-26S proteasome mediated protein turnover, such that the transcription by AhR is controlled at a physiologically adequate level. In addition to CYP1A1 induction, AhR mediates a broad range of biological responses to CYP1A1 inducers, typified by the environmental contaminant dioxin, via modulating gene expression. Thus, mechanistic studies of CYP1A1 induction have provided insights into P450 induction, PAH carcinogenesis, dioxin action, AhR function, and receptor-mediated mammalian gene expression.
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PMID:Induction of CYP1A1. The AhR/DRE paradigm: transcription, receptor regulation, and expanding biological roles. 1146 23


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