scholarly journals Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2659
Author(s):  
Jerry Vriend ◽  
Mark W. Nachtigal
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Ubiquitin Proteasome System ◽  
Differentially Expressed ◽  
Ovarian Carcinomas ◽  
Ubiquitin Proteasome Pathway ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

In this article, we reviewed the transcription of genes coding for components of the ubiquitin proteasome pathway in publicly available datasets of epithelial ovarian cancer (EOC). KEGG analysis was used to identify the major pathways distinguishing EOC of low malignant potential (LMP) from invasive high-grade serous ovarian carcinomas (HGSOC), and to identify the components of the ubiquitin proteasome system that contributed to these pathways. We identified elevated transcription of several genes encoding ubiquitin conjugases associated with HGSOC. Fifty-eight genes coding for ubiquitin ligases and more than 100 genes encoding ubiquitin ligase adaptors that were differentially expressed between LMP and HGSOC were also identified. Many differentially expressed genes encoding E3 ligase adaptors were Cullin Ring Ligase (CRL) adaptors, and 64 of them belonged to the Cullin 4 DCX/DWD family of CRLs. The data suggest that CRLs play a role in HGSOC and that some of these proteins may be novel therapeutic targets. Differential expression of genes encoding deubiquitinases and proteasome subunits was also noted.

scholarly journals Cyclin G2 Is Degraded through the Ubiquitin-Proteasome Pathway and Mediates the Antiproliferative Effect of Activin Receptor-like Kinase 7

2008 ◽  
Vol 19 (11) ◽  
pp. 4968-4979 ◽  
Author(s):  
Guoxiong Xu ◽  
Stefanie Bernaudo ◽  
Guodong Fu ◽  
Daniel Y. Lee ◽  
Burton B. Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Antiproliferative Effect ◽  
Ovarian Cancer Cells ◽  
Ubiquitin Proteasome Pathway ◽  
Receptor Like Kinase ◽  
Cyclin G2 ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

We have previously reported that Nodal, a member of the TGF-β superfamily, acts through activin receptor-like kinase 7 (ALK7) to inhibit ovarian cancer cell proliferation. To determine the mechanism underlying their effects, a cell cycle gene array was performed and cyclin G2 mRNA was found to be strongly up-regulated by Nodal and ALK7. To study the function and regulation of cyclin G2 in ovarian cancer cells, expression constructs were generated. We found that cyclin G2 protein level decreased rapidly after transfection, and this decrease was prevented by 26S proteasome inhibitors. Immunoprecipitation and pull-down studies showed that ubiquitin, Skp1, and Skp2 formed complexes with cyclin G2. Knockdown of Skp2 by siRNA increased, whereas overexpression of Skp2 decreased cyclin G2 levels. Nodal and ALK7 decreased the expression of Skp1 and Skp2 and increased cyclin G2 levels. Overexpression of cyclin G2 inhibited cell proliferation whereas cyclin G2-siRNA reduced the antiproliferative effect of Nodal and ALK7. Taken together, these findings provide strong evidence that cyclin G2 is degraded by the ubiquitin–proteasome pathway and that Skp2 plays a role in regulating cyclin G2 levels. Furthermore, our results also demonstrate that the antiproliferative effect of Nodal/ALK7 on ovarian cancer cells is in part mediated by cyclin G2.

Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9549-9549
Author(s):  
G. Antonini Cappellini ◽  
A. Borczuk ◽  
H. Kim ◽  
M. Hesdorffer ◽  
R. Taub ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Molecular Profiling ◽  
Peritoneal Mesothelioma ◽  
Differentially Expressed ◽  
Malignant Peritoneal Mesothelioma ◽  
Histologic Subtype ◽  
Ubiquitin Proteasome Pathway ◽  
Peritoneal Tissue ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

9549 Background: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm derived from cells lining serosal membranes. The characteristics of the epithelial (E) type MPM are distinct from those of the biphasic and sarcomatous (BS) type tumors. The goal of our study was to examine the molecular basis for this distinction. Methods: We used global molecular profiling with DNA microarrays to identify pathways associated with histologic subtype of 16 MPM tumor specimens acquired from patients entered into pilot multimodality protocols at our Institution. We performed immunohistochemistry on a tissue microarray and quantitative-real time PCR to validate the microarray results. Results: We performed average linkage agglomerative hierarchical clustering using microdissected MPM specimens and normal peritoneal tissue. The tumors segregated into two clades associated with histological subtype, which were distinct from the controls. 476 genes were differentially expressed between E and BS histologic classes (P < .001, with permutation test P value of .001). To identify biologically important differentially expressed genes and pathways, we examined the functional annotation of mesothelioma histologic subtype classifiers using the Pathway Comparison tool of BRB-Array. Among the differentially expressed categories was the ubiquitin-proteasome (UP) pathway, which was upregulated in BS tumors. Cytoxicity experiments by MTS assay indicated that, by the computation of combination indexes of activity, cells derived from BS tumors were exquisitely sensitive to sequential combination regimens containing the proteasome inhibitor (PI) bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of E tumor origin, was apoptosis. Conclusions: Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic and sarcomatous malignant peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients. No significant financial relationships to disclose.

Proteolysis, the ubiquitin-proteasome system, and renal diseases

2003 ◽  
Vol 285 (1) ◽  
pp. F1-F8 ◽  
Author(s):  
Richard Debigaré ◽  
S. Russ Price
Keyword(s):  
Renal Failure ◽  
Protein Degradation ◽  
Cell Function ◽  
Proteolytic Enzymes ◽  
Ubiquitin Proteasome System ◽  
Renal Diseases ◽  
Von Hippel Lindau ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Protein degradation is a critical process for the growth and function of cells. Proteolysis eliminates abnormal proteins, controls many cellular regulatory processes, and supplies amino acids for cellular remodeling. When substrates of proteolytic pathways are poorly recognized or there is mistiming of proteolysis, profound changes in cell function can occur. Based on these potential problems, it is not surprising that alterations in proteolytic enzymes/cofactors or in the structure of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with kidney cell malfunctions. Multiple pathways exist for protein degradation. The best-described proteolytic system is the ubiquitin-proteasome pathway, which requires ATP and degrades the bulk of cellular and some membrane proteins. This review will survey examples of renal abnormalities that are associated with defective protein degradation involving the ubiquitin-proteasome pathway. Loss of muscle mass associated with chronic renal failure, von Hippel-Lindau disease, Liddle syndrome, and ischemic acute renal failure will be discussed. These examples are indicative of the diverse roles of the ubiquitin-proteasome system in renal-associated pathological conditions.

scholarly journals Chronic contractile activity upregulates the proteasome system in rabbit skeletal muscle

2000 ◽  
Vol 88 (3) ◽  
pp. 1134-1141 ◽  
Author(s):  
George A. Ordway ◽  
P. Darrell Neufer ◽  
Eva R. Chin ◽  
George N. DeMartino
Keyword(s):  
Skeletal Muscle ◽  
Protein Degradation ◽  
Contractile Activity ◽  
Motor Nerve ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hydrolysis Of

Remodeling of skeletal muscle in response to altered patterns of contractile activity is achieved, in part, by the regulated degradation of cellular proteins. The ubiquitin-proteasome system is a dominant pathway for protein degradation in eukaryotic cells. To test the role of this pathway in contraction-induced remodeling of skeletal muscle, we used a well-established model of continuous motor nerve stimulation to activate tibialis anterior (TA) muscles of New Zealand White rabbits for periods up to 28 days. Western blot analysis revealed marked and coordinated increases in protein levels of the 20S proteasome and two of its regulatory proteins, PA700 and PA28. mRNA of a representative proteasome subunit also increased coordinately in contracting muscles. Chronic contractile activity of TA also increased total proteasome activity in extracts, as measured by the hydrolysis of a proteasome-specific peptide substrate, and the total capacity of the ubiquitin-proteasome pathway, as measured by the ATP-dependent hydrolysis of an exogenous protein substrate. These results support the potential role of the ubiquitin-proteasome pathway of protein degradation in the contraction-induced remodeling of skeletal muscle.

scholarly journals Interaction of U-box E3 ligase SNEV with PSMB4, the β7 subunit of the 20 S proteasome

2005 ◽  
Vol 388 (2) ◽  
pp. 593-603 ◽  
Author(s):  
Marlies LÖSCHER ◽  
Klaus FORTSCHEGGER ◽  
Gustav RITTER ◽  
Martina WOSTRY ◽  
Regina VOGLAUER ◽  
...  
Keyword(s):  
Immunofluorescence Microscopy ◽  
E3 Ligase ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Recognition of specific substrates for degradation by the ubiquitin–proteasome pathway is ensured by a cascade of ubiquitin transferases E1, E2 and E3. The mechanism by which the target proteins are transported to the proteasome is not clear, but two yeast E3s and one mammalian E3 ligase seem to be involved in the delivery of targets to the proteasome, by escorting them and by binding to the 19 S regulatory particle of the proteasome. In the present study, we show that SNEV (senescence evasion factor), a protein with in vitro E3 ligase activity, which is also involved in DNA repair and splicing, associates with the proteasome by directly binding to the β7 subunit of the 20 S proteasome. Upon inhibition of proteasome activity, SNEV does not accumulate within the cells although its co-localization with the proteasome increases significantly. Since immunofluorescence microscopy also shows increased co-localization of SNEV with ubiquitin after proteasome inhibition, without SNEV being ubiquitinated by itself, we suggest that SNEV shows E3 ligase activity not only in vitro but also in vivo and escorts its substrate to the proteasome. Since the yeast homologue of SNEV, Prp19, also interacts with the yeast β7 subunit of the proteasome, this mechanism seems to be conserved during evolution. Therefore these results support the hypothesis that E3 ligases might generally be involved in substrate transport to the proteasome. Additionally, our results provide the first evidence for a physical link between components of the ubiquitin–proteasome system and the spliceosome.

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