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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteasomes and ubiquitin (Ub) are essential components of the energy-dependent, nonlysosomal proteolytic pathway. To clarify the physiological role of this proteasome/Ub-dependent pathway, we meaured the levels of expressions of proteasomes and Ub in human renal cancers by Northern blot and immunochemical analyses. The mRNAs for two of the multiple subunits of proteasomes, C2 and C9, were expressed at abnormally high levels in most neoplastic lesions of patients with various primary renal cell carcinomas and in all renal cancer cell lines examined. However, no significant difference was found by enzyme immunoassay in the proteasomal contents of cancerous and normal parts of the kidney. The levels of mRNAs for the subunits of proteasomes were high in rapidly proliferating renal cells and appeared to be correlated with the activities of these cells for proteasome synthesis, but the cellular contents of proteasomes in these cells were normal, suggesting rapid turnover of proteasomes in rapidly proliferating cancer cells. Consistent with the increased expressions of proteasomal mRNAs, the expressions of three Ub genes, mono-UbA80, mono-UbA52, and poly-UbC, were found to be greatly increased in these renal cancer cells. Immunohistochemical staining of normal kidney showed that the levels of both proteasomes and Ub were high in cells of renal tubules and collecting ducts, but low in the glomerulus. The levels of both proteins appeared to be considerably increased in the nuclei of granular and clear carcinoma cells of the kidney. Moreover, the profiles of cellular proteins conjugated with Ub in normal kidney tissues were different from those in cancerous parts of the kidney and in established renal cancer cells. These results suggest that the proteasome- and ubiquitin-mediated system is functionally involved in the cancerous state in human kidney.
Cancer Res 1991 Dec 15
PMID:Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells. 166 Mar 45

Herbimycin A is an ansamycin antibiotic isolated as an agent that reverses morphological transformation induced by v-src. Although herbimycin A is widely used as a tool for inhibiting multiple tyrosine protein kinases and tyrosine kinase-activated signal transduction, its mechanism of action is not well defined and includes a decrease in both tyrosine kinase protein levels and activity (Uehara, Y., Murakami, Y., Sugimoto, Y., and Mizuno, S. (1989) Cancer Res. 49, 780-785). We now show that herbimycin A induces a profound decrease in the total cellular activity of transmembrane tyrosine kinase receptors, such as insulin-like growth factor, insulin, and epidermal growth factor receptors. A substantial proportion of the in vivo inhibition could be explained by an increase in the rate of degradation. The enhanced degradation of insulin-like growth factor-insulin receptor was prevented by inhibitors of the 20S proteasome, whereas neither lysosomotropic agents nor general serine- and cysteine-protease inhibitors were active in preventing receptor degradation induced by herbimycin A. Moreover, in a temperature-sensitive mutant cell line defective in the E1-catalyzed activation of ubiquitin, herbimycin A treatment at the restrictive temperature did not result in the degradation of insulin receptor. These results suggest that herbimycin A represents a novel class of drug that targets the degradation of tyrosine kinases by the 20S proteasome. The ubiquitin dependence of this process indicates that this degradation of tyrosine kinases might involve the 20S proteasome as the proteolytic core of the ubiquitin-dependent 26S protease.
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PMID:Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. 762 64

Group I Burkitt lymphoma (BL) lines retaining the original BL tumor cell phenotype are unable to present endogenously expressed antigens to HLA class I-restricted cytotoxic T cells (CTL) but can be recognized if the relevant HLA class I/peptide epitope complex is reconstituted at the cell surface by exogenous addition of synthetic target peptide. Endogenous antigen-processing function is restored in BL lines that have undergone Epstein-Barr virus (EBV)-induced drift in culture to the group III phenotype typically displayed by EBV-transformed lymphoblastoid cell lines (LCL) of normal B cell origin. We compared group I versus group III cells for their expression of proteasome components, transporter proteins and HLA-class I antigens, all of which are thought to be involved in the endogenous antigen processing pathway. By Western blot analysis, there were not consistent differences in the low molecular mass protein subunits of proteasomes (lmp)-2, lmp-7 and delta, although the mb-1 proteasome subunit was regularly present at higher levels in group I BL lines relative to group III lines or LCL. By contrast there were marked differences in the expression of peptide transporter-associated proteins (Tap), with down-regulation of Tap-1 and Tap-2 in 8/8 and 7/8 group I BL lines, respectively. Surface levels of HLA class I antigens were also consistently lower in group I cells; this was not associated with an intracellular accumulation of free HLA heavy chains, such as is seen in the Tap-deficient T2 processing-mutant line, but instead reflected a reduced rate of HLA class I synthesis in group I cells. Analysis of EBV gene transfectants of the B lymphoma lines BJAB and BL41 showed that the virus-encoded latent membrane protein-1 (LMP1), which is one of several EBV antigens expressed in group III but not in group I cells, was uniquely able to up-regulate expression both of the Tap proteins and HLA class I. Furthermore, this was accompanied by a restoration of antigen-processing function as measured by the ability of these cells to present an endogenously expressed viral antigen to CTL. These effects of LMP1 were similar to those induced in the same cell lines by interferon-gamma treatment. The results implicate both Tap and HLA class I expression as factors limiting the antigen-processing function of BL cells, and suggest that the accessibility of other EBV-associated malignancies to CTL surveillance may be critically dependent upon their LMP1 status.
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PMID:Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein-Barr virus latent membrane protein-1: coordinate up-regulation of peptide transporters and HLA-class I antigen expression. 777 41

The Yoshida sarcoma (YS) is characterized by growth as "free cells" in ascites. Long-survival Yoshida sarcoma (LY) variants, which develop after transplantation of YS into immunologically conditioned Donryu rats, in contrast, form "islands" in ascites. A representational difference analysis (RDA) approach was adopted to isolate genes differentially expressed between YS and LY variants to elucidate the molecular mechanism of their development. Fifteen clones presenting differences in expression were characterized. Nine genes (those encoding for the high-affinity IgE receptor gamma chain, pJG116 repetitive sequence, non neuronal enolase, proteasome subunit RC1, cytotoxic T lymphocyte-associated gene transcript CTLA-1, interleukin-2 receptor gamma chain, and three unknown sequences) expressed mRNA in YS, but showed lower or no expression of mRNA in LYs. The mRNAs of the other six genes (those encoding for cytokeratin 8, cytokeratin18 (Endo B), TIMP2 and three unknown sequences) were not found in YS, but were present in LYs. Interestingly, CTLA-1 is a non-epithelial (hematopoietic) cell-specific gene in terms of transcription, while cytokeratin 8 and cytokeratin 18 are both epithelium-specific genes. Immunohistochemically, YS expressed T-cell specific antigens CD2 and CD3, and T cell receptor beta and gamma chain genes were rearranged in YS, but not in LYs. Moreover, using restriction fragment length polymorphism probes, we found that LYs exhibited different cell lineage from YS. Thus, our present findings, unexpectedly, raise fundamental questions concerning the cellular origins of YS and LY variants rather than pointing to any specific mechanism to explain the LY phenomenon.
Jpn J Cancer Res 1994 Nov
PMID:Isolation of genes differentially expressed between the Yoshida sarcoma and long-survival Yoshida sarcoma variants: origin of Yoshida sarcoma revisited. 782 94

Little information is available on proteolytic pathways responsible for muscle wasting in cancer cachexia. Experiments were carried out in young rats to demonstrate whether a small (< 0.3% body weight) tumor may activate the lysosomal, Ca(2+)-dependent, and/or ATP-ubiquitin-dependent proteolytic pathway(s) in skeletal muscle. Five days after tumor implantation, protein mass of extensor digitorum longus and tibialis anterior muscles close to a Yoshida sarcoma was significantly reduced compared to the contralateral muscles. According to in vitro measurements, protein loss totally resulted from increased proteolysis and not from depressed protein synthesis. Inhibitors of lysosomal and Ca(2+)-dependent proteases did not attenuate increased rates of proteolysis in the atrophying extensor digitorum longus. Accordingly, cathepsin B and B+L activities, and mRNA levels for cathepsin B were unchanged. By contrast, ATP depletion almost totally suppressed the increased protein breakdown. Furthermore, mRNA levels for ubiquitin, 14 kDa ubiquitin carrier protein E2, and the C8 or C9 proteasome subunits increased in the atrophying muscles. Similar adaptations occurred in the muscles from cachectic animals 12 days after tumor implantation. These data strongly suggest that the activation of the ATP-ubiquitin-dependent proteolytic pathway is mainly responsible for muscle atrophy in Yoshida sarcoma-bearing rats.
Cancer Res 1994 Nov 01
PMID:Increased ATP-ubiquitin-dependent proteolysis in skeletal muscles of tumor-bearing rats. 792 98

The proteasome is a unique protease complex found in all eukaryotic cells and has multiple functions for essential activities. In this work we showed that it is expressed at high level in immature, rapidly growing cells, such as those in early embryonic tissues and cancer cells (Fig. 7). The increase of its expression is down-regulated on differentiation of the cells. However, lymphatic blastocytes grow rapidly and express high levels of proteasomes, but are differentiated. Therefore, the proteasome is not expressed at high levels only in immature cells, but is also involved specifically in nuclear activities of cells during rapid growth, possibly regulating proteinous factors in the cell cycle.
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PMID:Regulation of proteasome expression in developing and transformed cells. 835 6

In some human tumors, reduced or defective MHC class I surface expression has been attributed to functional deficiencies of the genes of the antigen-processing machinery, the proteasome subunits low molecular weight (LMP)-2 and LMP-7, as well as the peptide transporters associated with antigen processing (TAP)-1 and TAP-2. Using normal epithelial kidney cells (MZ1851NN) and renal cell carcinoma cell lines established from the primary tumor (MZ1851RC) and a lymph node metastasis (MZ1851LN) of the same patient, we investigated whether the modulation of MHC class I antigens, TAP and LMP molecules, occurs during transformation and subsequent progression. The mRNA and protein expression of MHC class I heavy and light chain TAP and LMP was strongly reduced in MZ1851RC when compared to the corresponding normal kidney cells MZ1851NN, and this suppression was even more pronounced in the metastatic cell line MZ1851LN. In addition, the activity of the TAP molecules, as measured by peptide translocation assays, was also markedly diminished in MZ1851RC compared to MZ1851NN cells and was further down-regulated in cells of the metastatic lesion. MHC class I surface expression was enhanced by either culturing MZ1851RC and MZ1851LN cells at 26 degrees C instead of 37 degrees C or by incubation of both cell lines with class I-specific binding peptides, whereas MHC class I surface expression of MZ1851NN cells was not affected under these culture conditions. IFN-alpha and in particular IFN-gamma treatment enhances the steady-state mRNA and/or protein levels of TAP, LMP, and MHC class I genes of MZ1851 cell lines but had no additional effect on the stability of MCH class I surface expression. These data indicate that malignant transformation and subsequent in vivo selection of renal tubular cells can lead to the recovery of carcinoma cells that show stable expression of an immune escape phenotype. Deficiencies associated with this phenotype involve all levels of the MHC class I-restricted antigen presentation machinery, are at least partially reversible by IFN treatment, and are even more pronounced in cells that had acquired metastatic potential.
Cancer Res 1996 Apr 15
PMID:Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression. 862 Apr 89

The levels of the tumor suppressor protein p53 are generally quite low in normal cells, due in part to its rapid turnover. Previous studies have implicated ubiquitin-dependent proteolysis in the turnover of wild-type p53 but have not established whether or not p53 is itself a substrate of the ubiquitin system. In this study, inhibitors of the 26S proteasome have been used to further explore the role of ubiquitin proteolysis in regulating p53 turnover. Increased levels of the tumor suppressor protein p53 were observed in normal cells, as well as in cells expressing the human papillomavirus 16 E6 oncoprotein, on exposure of the cells to proteasome inhibitors. Pulse-chase experiments indicated that the increased p53 levels resulted from stabilization of the protein. Furthermore, ubiquitin-p53 conjugates were detected in untreated as well as gamma-irradiated cells, indicating that ubiquitin-dependent proteolysis plays a role in the normal turnover of p53. Increased levels of the cyclin:cyclin-dependent kinase inhibitor p21, a downstream effector of p53 function, were also observed in proteasome inhibitor-treated cells, and this increase was due in part to an increase in p2l mRNA.
Cancer Res 1996 Jun 01
PMID:In vivo ubiquitination and proteasome-mediated degradation of p53(1). 865 11

Acute promyelocytic leukemia (APL) is associated with a chromosomal translocation t(15;17) and successfully differentiated by all-trans-retinoic acid (ATRA) in vivo as well as in vitro. The PML-retinoic acid receptor alpha (RARA) oncoprotein, which is generated by the translocation, blocks the differentiation, and ATRA is thought to modulate the dominant negative function of PML-RARA. However, the molecular effect of ATRA on PML-RARA is unknown. In this study, we showed by means of immunoblotting that the expression of PML-RARA decreased within 12 h in APL cells treated with ATRA at concentrations greater than 0.1 microM. The decrease of PML-RARA was associated with restoration of the normal subcellular PML localization. PML-RARA transcripts were not down-regulated by ATRA. However, lactacystin, a specific inhibitor of the proteasome, almost completely inhibited the decrease of PML-RARA. These data indicate that the PML-RARA degradation is accelerated by pharmacological concentrations of ATRA, suggesting that ATRA allows APL cells to differentiate by relieving the differentiation block.
Cancer Res 1996 Jul 01
PMID:Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. 867 46

Rb protein is a critical regulator of entry into the cell cycle, and loss of Rb function by deletions, mutations, or interaction with DNA viral oncoproteins leads to oncogenic transformation. We have shown that the human papilloma virus (HPV)-16 E7 gene is sufficient to induce the immortalization of mammary epithelial cells (MECs). Surprisingly, the steady-state level of Rb protein in these immortal cells was drastically decreased. Here, we used pulse-chase analysis to show that the in vivo loss of Rb protein in E7-immortalized MECs is a consequence of enhanced degradation. Expression of HPV16 E7 in a cell line with a temperature-sensitive mutation in the E1 enzyme of the ubiquitin pathway demonstrated that degradation of Rb was ubiquitin dependent. Treatment of E7-immortalized MECs with aldehyde inhibitors of proteasome-associated proteases led to a marked stabilization of Rb protein, particularly the hypophosphorylated form. Taken together, our results provide evidence for HPV-16 E7-induced enhanced degradation of Rb protein via a ubiquitin-proteasome pathway and suggest a second mechanism of oncogenic transformation by E7, in addition to its previously identified ability to sequester Rb from E2F. Our analyses also show that normal Rb levels are regulated by the ubiquitin-proteasome degradation pathway.
Cancer Res 1996 Oct 15
PMID:E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. 884 Sep 74


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