Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The membrane-bound complement regulators decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), and CD59 are broadly expressed proteins that act together to protect host tissues from autologous complement. Comparison of expression profiles of these proteins between normal and pathological tissues could reveal a mechanism by which tumor cells evade complement-mediated killing. Expression of the regulators was therefore examined in the normal human uterine cervix, in cervical intraepithelial neoplasia (CIN; n = 23), and in cervical squamous carcinomas (n = 6). DAF and MCP were reciprocally expressed in normal ectocervical epithelium. MCP was confined predominantly to the basal and parabasal layers with more extensive expression in metaplastic squamous epithelium. An apparent expansion in MCP expression was observed in more severe premalignant lesions whereas cervical carcinoma were uniformly MCP positive. By contrast, DAF expression appeared unaltered in premalignant lesions and variable in carcinomas. However, increased DAF was observed in stromal cells directly adjacent to infiltrating tumor cells. A low molecular weight DAF product was detected in tumors, and preliminary evidence suggests this may be derived from stromal cells. Overall, changes in expression of C3 convertase regulators in both the stromal and epithelial compartments may be important for evasion of immune surveillance in cervical cancer.
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PMID:Expression of the complement regulatory proteins decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and CD59 in the normal human uterine cervix and in premalignant and malignant cervical disease. 935 72

Rapid degradation of wild-type p53 in the human uterine cervix is induced by the infection of high-risk human papilloma virus (HPV) types 16 and 18. HPV-E6 protein plays a critical role in the poly-ubiquitination of wild-type p53 by mediating the association of p53 with E6-associated protein (E6AP). As a result, the poly-ubiquitinated p53 is rapidly and selectively degraded by the 26S proteasome. We have established a high throughput assay system to monitor poly-ubiquitination of wild-type p53 using a new fluorescence homogeneous technology known as Homogeneous Time-Resolved Fluorescence (HTRFTM). The Europium Cryptate [Eu(K)]-labeled ubiquitins are incorporated into poly-ubiquitin chains conjugated with the biotinylated p53. In the HTRF assay, Europium cryptate-labeled ubiquitin and streptavidin-labeled allophycocyanin (XL665) are used as the fluorescence donor and acceptor, respectively. The biotinylated p53 is ubiquitinated by ubiquitination enzymes, then by the addition of streptavidin-labeled XL665, the donor and acceptor molecules are brought in close proximity, thereby generating fluorescent signals. This time-resolved fluorescence assay system shows a sufficient signal for its application in synthetic compound screening and having almost the same level of sensitivity as that monitored by the scintillation proximity assay (SPA) using 125I-labeled ubiquitin. The detection of poly-ubiquitination of wild-type p53 by using the HTRFTM or SPA systems described here is much easier and quicker than by using conventional methods. Therefore, these new systems would be appropriate for high throughput screening of compounds for the discovery of new inhibitors of poly-ubiquitination of wild-type p53.
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PMID:Application of homogeneous time-resolved fluorescence (HTRFTM) to monitor poly-ubiquitination of wild-type p53. 1053 89

A novel cytoplasmic structure has been recently characterized by confocal and electron microscopy in H. pylori-infected human gastric epithelium, as an accumulation of barrel-like proteasome reactive particles colocalized with polyubiquitinated proteins, H. pylori toxins and the NOD1 receptor. This proteasome particle-rich cytoplasmic structure (PaCS), a sort of focal proteasome hyperplasia, was also detected in dysplastic cells and was found to be enriched in SHP2 and ERK proteins, known to play a role in H. pylori-mediated gastric carcinogenesis. However, no information is available on its occurrence in neoplastic growths. In this study, surgical specimens of gastric cancer and various other human epithelial neoplasms have been investigated for PaCSs by light, confocal and electron microscopy including correlative confocal and electron microscopy (CCEM). PaCSs were detected in gastric cohesive, pulmonary large cell and bronchioloalveolar, thyroid papillary, parotid gland, hepatocellular, ovarian serous papillary, uterine cervix and colon adenocarcinomas, as well as in pancreatic serous microcystic adenoma. H. pylori bodies, their virulence factors (VacA, CagA, urease, and outer membrane proteins) and the NOD1 bacterial proteoglycan receptor were selectively concentrated inside gastric cancer PaCSs, but not in PaCSs from other neoplasms which did, however, retain proteasome and polyubiquitinated proteins reactivity. No evidence of actual microbial infection was obtained in most PaCS-positive neoplasms, except for H. pylori in gastric cancer and capsulated bacteria in a colon cancer case. Particle lysis and loss of proteasome distinctive immunoreactivities were seen in some tumour cell PaCSs, possibly ending in sequestosomes or autophagic bodies. It is concluded that PaCSs are widely represented in human neoplasms and that both non-infectious and infectious factors activating the ubiquitin-proteasome system are likely to be involved in their origin. PaCS detection might help clarify the role of the ubiquitin-proteasome system in carcinogenesis.
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PMID:Proteasome particle-rich structures are widely present in human epithelial neoplasms: correlative light, confocal and electron microscopy study. 2169 63

Although the prognosis of uterine cervical cancer has improved due to the advances of treatment modalities, survival of recurrent or metastatic cervical cancer remains poor. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer is disappointing. Inactivation of tumor suppressors through ubiquitin-mediated degradation by human papillomavirus is known to be a critical step in the carcinogenesis of uterine cervix. Bortezomib, a selective inhibitor of the proteasome, has been shown to inhibit the growth of several solid tumors. To determine the role of bortezomib in cervical cancer as a chemotherapeutic agent, we studied its biological properties. Bortezomib efficiently inhibited the proteasomal activities in cervical cancer cells, and an increased expression of tumor suppressors such as p53, hDlg and hScrib became evident. In addition, sequential or concomitant treatment of bortezomib and cisplatin stimulated the expression of p53, hScrib and p21 and the stimulation was markedly influenced by the order of drugs in HeLa cells. We further confirmed that the concomitant use of bortezomib and cisplatin has synergistic inhibitory effects on the growth of xenograft tumors derived from HeLa cells. Our data establish the possibility that the concomitant use of bortezomib and cisplatin could be an alternative choice in cases resistant to conventional chemotherapy, and sequential effects must be considered for advanced and therapy-resistant cervical cancer patients.
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PMID:Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer cell lines. 2306 81

Squamous carcinomas of the head and neck area are carcinomas that were traditionally associated with alcohol and tobacco abuse. More recently, a pathogenic relationship of oncogenic human papilloma viruses (HPV) with head and neck cancer of the oropharynx and the base of the tongue has been revealed. Two proteins of HPV, E6 and E7, are involved in neoplastic transformation not only in the head and neck but in other locations, where these epitheliotropic viruses cause carcinomas, such as the uterine cervix and the anal region. The E6 viral protein associates with cellular E3 ubiquitin ligase E6-AP and promotes degradation of tumour suppressor p53 by the proteasome. This molecular event reveals the important role that the ubiquitin-proteasome system (UPS) plays in the pathogenesis of head and neck cancer. The role of this system in head and neck carcinogenesis is not restricted to the destruction of p53 but extends to most, if not all, signaling pathways that regulate carcinogenesis in this location. These roles are reviewed here and implications for treatment are discussed.
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PMID:Ubiquitination and the ubiquitin - proteasome system in the pathogenesis and treatment of squamous head and neck carcinoma. 2402 78

High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer.
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PMID:Ubiquitination of the HPV Oncoprotein E6 Is Critical for E6/E6AP-Mediated p53 Degradation. 3174 82