Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The EphA2 receptor tyrosine kinase is an attractive therapeutic target that is commonly overexpressed on solid tumors, with the degree of overexpression associated with disease progression, metastatic potential, and poor prognosis. Agonistic mAbs or ligand (ephrinA1)-Fc fusion protein are capable of inducing EphA2 internalization and degradation, thereby (at least transiently) eliminating the influence of this oncoprotein. We and others have also shown that EphA2 contains multiple peptide epitopes that can be recognized by effector CD4(+) and CD8(+) T cells isolated from tumor-bearing patients. Herein, we show that "agonist" reagents that trigger the proteasome-dependent degradation of tumor cell EphA2 result in the improved presentation of peptides derived from (both the extracellular and intracellular domains of) EphA2 in MHC class I complexes expressed on the tumor cell membrane for at least 48 h, as manifested by increased recognition by EphA2-specific CD8(+) T cells in vitro. We also observed that while delivery of ephrinA1-Fc fusion protein or agonist mAb into EphA2(+) tumor lesions promotes EphA2 degradation in situ, this single administration of agent does not dramatically alter tumor progression in a humanized SCID model. However, when combined with the adoptive transfer of normally nontherapeutic (human) anti-EphA2 CD8(+) CTL, this dual-agent regimen results in complete tumor eradication. These results suggest that strategies targeting the conditional proteasome-mediated destruction of tumor cell EphA2 may enable EphA2-specific CD8(+) T cells (of modest functional avidity) to realize improved therapeutic potential.
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PMID:Enhancement in specific CD8+ T cell recognition of EphA2+ tumors in vitro and in vivo after treatment with ligand agonists. 1901 61

Genetic and biochemical studies have provided considerable insight into the multiple functions of cyclin-dependent kinase subunit (cks)1 in cell division cycle. In addition to enhanced substrate targeting by specific ubiquitin ligases SCF(skp2) and APC/C, its direct interaction with proteasome components normalizes multiple cell cycle regulators. Importantly, it also acts as a transcriptional regulator. cks1 overexpression reflects poor prognosis in malignancy thus indicating its possible role in tumour diagnosis and management. The present review compiles the multiple functional roles of cks1 in cell division with specific emphasis on its molecular mechanisms. Its docking functions and the possible downstream proteolytic and transcriptional targets are described. The spatial configuration of cks1-cdk2 complex and the structural organization of cks1-p27-skp2 assembly required for p27 ubiquitination are discussed in detail. In addition to enhanced p27 degradation, the possible other mechanisms which underlie its pathological functions in human cancer progression are also discussed. Though there are apparent gaps in information, the turnover mechanism of cks1 is well addressed and presents opportunity to exploit the target for disease management.
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PMID:Loss of cks1 homeostasis deregulates cell division cycle. 1922 69

The epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-beta. Expression of E-cadherin, a representative epithelial marker, is repressed through transcriptional reduction by TGF-beta. Here, we show that endocytosis of cell surface E-cadherin during EMT induced by TGF-beta and during scattering induced by hepatocyte growth factor (HGF) can be blocked by inhibiting proteasome with lactacystin and MG132 in normal epithelial cells and in cancer cells. Although loss of cell surface E-cadherin following TGF-beta treatment induced translocation of beta-catenin, an E-cadherin-anchoring molecule, to the nucleus, proteasome inhibition prevented this process and resulted in co-localization of beta-catenin with E-cadherin at the cell surface, leading to establishment of cell-cell adhesion. However, promotion of cell migration by TGF-beta was not significantly affected by proteasome inhibition. Proteasome-dependent events thus appear to be involved in stabilization of cell surface E-cadherin.
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PMID:Regulation of the stability of cell surface E-cadherin by the proteasome. 1924 96

A subset of Eph receptors and their corresponding ligands are commonly expressed in tumor cells where they mediate biological processes such as cell migration and adhesion, whereas their expression in endothelial cells promotes angiogenesis. In particular, the tumor-specific up-regulation of EphA2 confers properties of increased cellular motility, invasiveness, tumor angiogenesis, and tumor progression, and its overexpression correlates with poor prognosis in several cancer types. The cellular chaperone Hsp90 also plays a significant role in regulating cell migration and angiogenesis, although the full repertoire of motility driving proteins dependent on Hsp90 function remain poorly defined. We explored the hypothesis that Hsp90 may regulate the activity of EphA2 and examined the potential relationship between EphA2 receptor signaling and chaperone function. We show that geldanamycin, an Hsp90 antagonist, dramatically destabilizes newly synthesized EphA2 protein and diminishes receptor levels in a proteasome-dependent pathway. In addition, geldanamycin treatment impairs EphA2 signaling, as evidenced by a decrease in ligand-dependent receptor phosphorylation and subsequent cell rounding. Therefore, Hsp90 exerts a dual role in regulating the stability of nascent EphA2 protein and maintaining the signaling capacity of the mature receptor. Our findings also suggest that the geldanamycin-dependent mitigation of EphA2 signaling in receptor-overexpressing cancer cells may be sufficient to recapitulate the antimotility effects of this drug. Finally, the identification of a pharmacologic approach to suppress EphA2 expression and signaling highlights the attractive possibility that Hsp90 inhibitors may have clinical utility in antagonizing EphA2-dependent tumorigenic progression.
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PMID:Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis. 1956 82

We performed a comprehensive analysis of a literature-mined human signaling network by integrating data on ubiquitin-mediated protein half-lives. We found that proteins with very long half-lives are connected to form a network backbone, while proteins with short and medium half-lives preferentially attach to the network backbone and scatter throughout the network. Furthermore, proteins with short and medium half-lives are mutually exclusive in network neighbors. Short half-life proteins are enriched in the upstream portion of the network, suggesting that ubiquitination might help initiate signal processing and specificity. We also discovered that ubiquitination preferentially occurs in positive regulatory loops. Furthermore, these loops predominately induce or positively regulate apoptosis, a major component in cancer signaling. These results lead us to discover that the highly expressed genes involved in the common machinery of ubiquitination, the 26S proteasome genes, are significantly correlated with tumor progression and metastasis. Furthermore, expression of the 26S proteasome gene set predicts the clinical outcome of breast cancer patients. Our findings have implications for the development of cancer treatments and prognostic markers focused on the ubiquitination machinery.
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PMID:Signaling network analysis of ubiquitin-mediated proteins suggests correlations between the 26S proteasome and tumor progression. 1959 71

The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed.
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PMID:The ubiquitin proteasome system in neuropathology. 1959 29

Although hypoxia-inducible factor-1alpha (HIF-1alpha) has long been intensively investigated as a drug target by interfering with its expression or transcriptional function, the regulatory mechanisms of HIF-1alpha remain to be further clarified. We report here that c-Jun associates with HIF-1alpha via its oxygen-dependent degradation domain, masks the sites for ubiquitination, and thus protects HIF-1alpha from proteasome-executing degradation. All of these together resulted in the stabilization and accumulation of HIF-1alpha, consequently promoting the transcription of its target gene and driving angiogenesis-related events. The stabilization of HIF-1alpha was dependent on the domains of c-Jun for DNA binding and heterodimerization but independent of the Ser(63/73) phosphorylation that is critical for transcriptional function. These findings highlight a previously unrecognized nontranscriptional function of c-Jun on the one hand and a distinct regulatory mechanism of HIF-1alpha activity on the other, consequently offering profound mechanistic insights into multiple events simultaneously involving both c-Jun and HIF-1alpha in tumor progression.
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PMID:c-Jun protects hypoxia-inducible factor-1alpha from degradation via its oxygen-dependent degradation domain in a nontranscriptional manner. 1973 58

The anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase functions with the E2 ubiquitin-conjugating enzyme UbcH10 in the orderly progression through mitosis by marking key mitotic regulators for destruction by the 26-S proteasome. UbcH10 is overexpressed in many human cancer types and is associated with tumor progression. However, whether UbcH10 overexpression causes tumor formation is unknown. To address this central question and to define the molecular and cellular consequences of UbcH10 overexpression, we generated a series of transgenic mice in which UbcH10 was overexpressed in graded fashion. In this study, we show that UbcH10 overexpression leads to precocious degradation of cyclin B by the APC/C, supernumerary centrioles, lagging chromosomes, and aneuploidy. Importantly, we find that UbcH10 transgenic mice are prone to carcinogen-induced lung tumors and a broad spectrum of spontaneous tumors. Our results identify UbcH10 as a prominent protooncogene that causes whole chromosome instability and tumor formation over a wide gradient of overexpression levels.
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PMID:Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. 2006 91

Transglutaminase 2 (TGase2) is a calcium-dependent, cross-linking enzyme that catalyzes iso-peptide bond formation between peptide-bound lysine and glutamine residues. TGase 2 can activate NF-kappaB through the polymerization-mediated depletion of I-kappaBalpha without IKK activation. This NF-kappaB activation mechanism is associated with drug resistance in cancer cells. However, the polymers cannot be detected in cells, while TGase 2 over-expression depletes free I-kappaBalpha, which raises the question of how the polymerized I-kappaBalpha can be metabolized in cells. Among proteasome, lysosome and calpain systems, calpain inhibition was found to effectively increase the accumulation of I-kappaBalpha polymers in MCF7 cells transfected with TGase 2, and induced high levels of I-kappaBalpha polymers as well in MDA-MB-231 breast cancer cells that naturally express a high level of TGase 2. Inhibition of calpain also boosted the level of I-kappaBalpha polymers in HEK-293 cells in case of TGase 2 transfection either with I-kappaBalpha or I-kappaBalpha mutant (S32A, S36A). Interestingly, the combined inhibition of calpain and the proteasome resulted in an increased accumulation of both I-kappaBalpha polymers and I-kappaBalpha, concurrent with an inhibition of NF-kappaB activity in MDA-MB-231 cells. This suggests that mu-calpain proteasome-dependent I-kappaBalpha polymer degradation may contribute to cancer progression through constitutive NF-kappaB activation.
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PMID:I-kappaBalpha depletion by transglutaminase 2 and mu-calpain occurs in parallel with the ubiquitin-proteasome pathway. 2065 25

The cancer secretome is a rich repository in which to mine useful information for both cancer biology and clinical oncology. To help understand the mechanisms underlying the progression of pancreatic cancer, we characterized the secretomes of four human pancreatic ductal adenocarcinoma (PDAC) cell lines versus a normal counterpart. To this end, we used a proteomic workflow based on high-confidence protein identification by mass spectrometry, semiquantitation by a label-free approach, and network enrichment analysis by a system biology tool. Functional networks significantly enriched with PDAC-dysregulated proteins included not only expected alterations within key mechanisms known to be relevant for tumor progression (e.g., cell-cell/cell-matrix adhesion, extracellular matrix remodeling, and cytoskeleton rearrangement), but also other extensive, coordinated perturbations never observed in pancreatic cancer. In particular, we highlighted perturbations possibly favoring tumor progression through immune escape (i.e., inhibition of the complement system, deficiency of selected proteasome components within the antigen-presentation machinery, and inhibition of T cell cytoxicity), and a defective protein folding machinery. Among the proteins found concordantly oversecreted in all of our PDAC cell lines, many are reportedly overexpressed in pancreatic cancer (e.g., CD9 and Vimentin), while others (PLOD3, SH3L3, PCBP1, and SFRS1) represent novel PDAC-secreted proteins that may be worth investigating.
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PMID:Secretome analysis of multiple pancreatic cancer cell lines reveals perturbations of key functional networks. 2068 67


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