scholarly journals Antimicrobial Peptide Epinecidin-1 Modulates MyD88 Protein Levels via the Proteasome Degradation Pathway

Marine Drugs ◽  
2017 ◽  
Vol 15 (11) ◽  
pp. 362 ◽  
Author(s):  
Bor-Chyuan Su ◽  
Jyh-Yih Chen
Keyword(s):  
Antimicrobial Peptide ◽  
Degradation Pathway ◽  
Proteasome Degradation ◽  
Protein Levels ◽  
Myd88 Protein

The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

2007 ◽  
Vol 179 (4) ◽  
pp. 2089-2096 ◽  
Author(s):  
Giovanna Peruzzi ◽  
Rosa Molfetta ◽  
Francesca Gasparrini ◽  
Laura Vian ◽  
Stefania Morrone ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Degradation Pathway ◽  
Proteasome Degradation ◽  
Adaptor Molecule ◽  
Ubiquitin Proteasome

scholarly journals FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Mei Ji ◽  
Zhao Zhao ◽  
Yue Li ◽  
Penglin Xu ◽  
Jia Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Inverse Correlation ◽  
Degradation Pathway ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Poor Overall Survival ◽  
Protein Levels ◽  
Ubiquitin E3 Ligase ◽  
Ovarian Tumorigenesis ◽  
F Box Protein

AbstractRNASET2 (Ribonuclease T2) functions as a tumor suppressor in preventing ovarian tumorigenesis. However, the mechanisms underlying the regulation of RNASET2 protein are completely unknown. Here we identified the F-box protein FBXO6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin E3 ligase for RNASET2. We found that the interaction between FBXO6 and RNASET2 induced RNASET2 instability through the ubiquitin-mediated proteasome degradation pathway. FBXO6 promoted K48-dependent ubiquitination of RNASET2 via its FBA domain. Through analysis of the TCGA dataset, we found that FBXO6 was significantly increased in ovarian cancer tissues and the high expression of FBXO6 was related to the poor overall survival (OS) of ovarian cancer patients at advanced stages. An inverse correlation between the protein levels of FBXO6 and RNASET2 was observed in clinic ovarian cancer samples. Depletion of FBXO6 promoted ovarian cancer cells proliferation, migration, and invasion, which could be partially reversed by RNASET2 silencing. Thus, our data revealed a novel FBXO6-RNASET2 axis, which might contribute to the development of ovarian cancer. We propose that inhibition of FBXO6 might represent an effective therapeutic strategy for ovarian cancer treatment.

422 URSODEOXYCHOLIC ACID MODULATES THE UBIQUITIN-PROTEASOME DEGRADATION PATHWAY OF P53

2008 ◽  
Vol 48 ◽  
pp. S162-S163
Author(s):  
J.D. Amaral ◽  
R.E. Castro ◽  
S. Sola ◽  
C.M.P. Rodrigues
Keyword(s):  
Ursodeoxycholic Acid ◽  
Degradation Pathway ◽  
Proteasome Degradation ◽  
Ubiquitin Proteasome

scholarly journals Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders

2020 ◽  
Vol 117 (22) ◽  
pp. 12121-12130
Author(s):  
Yao-Cheng Li ◽  
Nikki K. Lytle ◽  
Seth T. Gammon ◽  
Luke Wang ◽  
Tikvah K. Hayes ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Developmental Disorders ◽  
Degradation Pathway ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Ras Proteins ◽  
Ras Protein ◽  
Protein Levels ◽  
Ras Family ◽  
Ras Isoforms

HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS–RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome–lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.

scholarly journals Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1

2010 ◽  
Vol 206 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Sanhua Leng ◽  
Wenshuo Zhang ◽  
Yanbin Zheng ◽  
Ziva Liberman ◽  
Christopher J Rhodes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Molecular Mechanism ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Insulin Receptor Substrate ◽  
Glycogen Synthase Kinase 3Β ◽  
Proteasome Degradation ◽  
Protein Levels

High glucose (HG) has been shown to induce insulin resistance in both type 1 and type 2 diabetes. However, the molecular mechanism behind this phenomenon is unknown. Insulin receptor substrate (IRS) proteins are the key signaling molecules that mediate insulin's intracellular actions. Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. We have identified glycogen synthase kinase 3β (GSK3β or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine332 phosphorylation, ubiquitination, and degradation of IRS1. Overexpression of IRS1 with mutation of serine332 to alanine partially prevents HG-induced IRS1 degradation. Furthermore, overexpression of constitutively active GSK3β was sufficient to induce IRS1 degradation. Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3β contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1.

scholarly journals Molecular Mechanism of Insulin-Induced Degradation of Insulin Receptor Substrate 1

2002 ◽  
Vol 22 (4) ◽  
pp. 1016-1026 ◽  
Author(s):  
Rachel Zhande ◽  
John J. Mitchell ◽  
Jiong Wu ◽  
Xiao Jian Sun
Keyword(s):  
Insulin Receptor ◽  
Molecular Mechanism ◽  
Degradation Pathway ◽  
In Vivo Studies ◽  
Temperature Sensitive ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Proteasome Degradation ◽  
Ubiquitin Proteasome

ABSTRACT Insulin receptor substrate 1 (IRS-1) plays an important role in the insulin signaling cascade. In vitro and in vivo studies from many investigators have suggested that lowering of IRS-1 cellular levels may be a mechanism of disordered insulin action (so-called insulin resistance). We previously reported that the protein levels of IRS-1 were selectively regulated by a proteasome degradation pathway in CHO/IR/IRS-1 cells and 3T3-L1 adipocytes during prolonged insulin exposure, whereas IRS-2 was unaffected. We have now studied the signaling events that are involved in activation of the IRS-1 proteasome degradation pathway. Additionally, we have addressed structural elements in IRS-1 versus IRS-2 that are required for its specific proteasome degradation. Using ts20 cells, which express a temperature-sensitive mutant of ubiquitin-activating enzyme E1, ubiquitination of IRS-1 was shown to be a prerequisite for insulin-induced IRS-1 proteasome degradation. Using IRS-1/IRS-2 chimeric proteins, the N-terminal region of IRS-1 including the PH and PTB domains was identified as essential for targeting IRS-1 to the ubiquitin-proteasome degradation pathway. Activation of phosphatidylinositol 3-kinase is necessary but not sufficient for activating and sustaining the IRS-1 ubiquitin-proteasome degradation pathway. In contrast, activation of mTOR is not required for IRS-1 degradation in CHO/IR cells. Thus, our data provide insight into the molecular mechanism of insulin-induced activation of the IRS-1 ubiquitin-proteasome degradation pathway.

Increased Expression of Proteasome-Related Genes In Patients with Primary Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4117-4117
Author(s):  
Vibe Skov ◽  
Thomas Stauffer Larsen ◽  
Mads Thomassen ◽  
Caroline Riley ◽  
Morten Krogh Jensen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Whole Blood ◽  
Proteasome Inhibitor ◽  
Single Gene ◽  
Primary Myelofibrosis ◽  
Degradation Pathway ◽  
Gene Analysis ◽  
Proteasome Degradation ◽  
Nf Kappab

Abstract Abstract 4117 Introduction: The proteasome is an ubiquituous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis, and angiogenesis. Since these pathways and functions are often deregulated in cancer cells, inhibition of the proteasome is an attractive potential anticancer therapy. Bortezomib (Velcade, formerly PS-341) is an extremely potent and selective proteasome inhibitor that shows strong activity against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-kappaB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Bortezomib is a well-established treatment in multiple myeloma and studies are focusing in the potential benefit of bortezomib in other haematological malignancies, including malignant lymphomas. Since the NF-kappaB pathway is considered to be implicated in the abnormal release of cytokines in primary myelofibrosis (PMF), the proteasome inhibitor bortezomib might be a potential therapy. In a murine model, bortezomib has been demonstrated to inhibit thrombopoietin (TPO)-induced NF-kappaB activation in megakaryocytes and to reduce myeloproliferation induced by high TPO levels. Accordingly, from in vitro studies it was concluded that bortezomib might be a promising therapy for future treatment of PMF patients. Surprisingly, however, these encouraging results have not been achieved in clinical trials testing bortezomib in patients with myelofibrosis. We have performed gene expression profiling of patients with PMF and in patients with other chronic myeloproliferative neoplasms (CMPNs) in order to describe aberrant genes in the proteasome pathway in PMF. Materials and methods: The HG-U133 Plus 2.0 microarray from Affymetrix was used to profile expression of 38500 genes in whole blood from 70 patients with CMPNs, including 9 patients with PMF and 61 patients with other CMPNs. All patients were diagnosed according to the WHO criteria of a CMPN (ET=19, PV=41, PMF=9). The patients were diagnosed and followed in two institutions. Most patients were studied on cytoreductive therapy, which for the large majority included hydroxyurea. Total RNA was purified from whole blood and amplified to biotin-labeled aRNA and hybridized to microarray chips. Differences in gene expression between the two groups were calculated for each gene in the dataset by using Welch two sample t test, and the Benjamini Hochberg method was applied to control for multiple hypothesis testing (false discovery rate (FDR) < 0.05). Data were integrated with biological pathways and networks using Gene Microarray Pathway Profiler (GenMAPP 2.1) and Cytoscape 2.6.3, respectively. Hypothesis driven discovery was used to find significantly differentially expressed genes and pathways associated with PMF. Results: Single gene analysis demonstrated significantly elevated expression of seventeen proteasomal subunit genes in patients with PMF (PSMA1, PSMA2, PSMA6, PSMA7, PSMB4, PSMB5, PSMB6, PSMB7, PSMC2, PSMC3, PSMD10, PSMD14, PSMD4, PSMD8, PSMD9, PSMG1, and PSMG3 (FDR < 0.05). Only one gene, PSMB4, was significantly downregulated (FDR < 0.05). Global pathway analysis showed a significant upregulation of the proteasome degradation pathway (adjusted P < 0.03), and the network analysis revealed a significant subnetwork only composed of upregulated genes (CDC25A, CDC6, CDT1, GMNN, ORC1L, PSMA6, PSMA7, PSMB5, PSMB6, PSMB7, PSMC3, PSMD5, PSMD8, PSMD9, PSMD14) of which 10 were proteasomal genes (Z=2.6). Conclusion: In this study, we have for the first time described the gene signature of the proteasome in peripheral blood cells from patients with myelofibrosis and patients with ET and PV. Using single gene analysis, global pathway and network analysis, we found significant upregulation of the proteasomal transcriptome in patients with PMF as compared to patients with ET and PV as a group. This study has added new important information of the genes involved in the upregulation of the proteasome degradation pathway in these patients. Disclosures: No relevant conflicts of interest to declare.

RAB14 and RAB5 Gtpases Regulate Human Erythropoiesis, Potentially Via Opposing Roles in Endosomal Recycling

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 937-937
Author(s):  
MinJung Kim ◽  
Tami J. Kingsbury ◽  
Wen-Chih Cheng ◽  
Yee Sun Tan ◽  
Brittany M. Taylor ◽  
...  
Keyword(s):  
Cell Surface ◽  
Conflicts Of Interest ◽  
Degradation Pathway ◽  
Rab Gtpases ◽  
Recycling Endosome ◽  
Hematopoietic Stem ◽  
Surface Receptors ◽  
Protein Levels ◽  
Endosomal Recycling ◽  
Model Cell

Abstract Previously, we reported that the erythroid-expressed miRs, miR-144 and miR-451, target the RAB14 GTPase during human erythropoiesis in the human TF1 erythropoietic model cell line and in primary CD34+ hematopoietic stem-progenitor cells. In response to erythropoietin, endogenous RAB14 levels decreased during erythropoiesis, and RAB14 knockdown increased the numbers of erythroid (CD34- CD71hi CD235ahi) cells, increased b-hemoglobin expression, and decreased ETO2 expression (Kim, BJH, 2015). Taken together, our findings revealed that RAB14 functions as a physiologic inhibitor of human erythropoiesis. RAB GTPases comprise a >60 member subfamily of the large RAS oncogene family, and multiple RAB GTPases play important roles in vesicle trafficking, signal transduction and receptor recycling. RAB14 is a component of the intermediate compartment of the endosomal recycling pathway, between the RAB4/RAB5-dependent early endosome and the RAB11-dependent recycling endosome (Linford, Dev. Cell, 2012). The RAB GTPases are responsible for directing cargo proteins to the recycling vs. degradation pathway during endosome maturation. To test the role of another endosomal RAB GTPases in human erythropoiesis, we examined the consequences of knocking down RAB5 protein levels. In contrast to our findings with RAB14, knockdown of RAB5C decreased the numbers of erythroid cells generated during erythropoiesis, indicating that RAB5C enhances physiologic erythropoiesis. Consistent with this observation, mRNA and protein levels for all three RAB5 isoforms (i.e. RAB5A, B, C) increased during erythropoiesis. The opposing erythropoietic effects of RAB14 and RAB5 GTPases may be due to their contrary roles in endosomal recycling, in that internalization of cell surface receptors is dependent on RAB5 GTPase, whereas RAB14 GTPase is involved in recycling of receptors back to the cell surface. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Constitutive Turnover of Cyclin E by Cul3 Maintains Quiescence

2007 ◽  
Vol 27 (10) ◽  
pp. 3651-3666 ◽  
Author(s):  
Justina D. McEvoy ◽  
Uta Kossatz ◽  
Nisar Malek ◽  
Jeffrey D. Singer
Keyword(s):  
Mammalian Cells ◽  
Gene Deletion ◽  
Cyclin E ◽  
E3 Ligase ◽  
Degradation Pathway ◽  
Conditional Knockout ◽  
Protein Levels ◽  
Primary Fibroblasts

ABSTRACT Two distinct pathways for the degradation of mammalian cyclin E have previously been described. One pathway is induced by cyclin E phosphorylation and is dependent on the Cul1/Fbw7-based E3 ligase. The other pathway is dependent on the Cul3-based E3 ligase, but the mechanistic details of this pathway have yet to be elucidated. To establish the role of Cul3 in the degradation of cyclin E in vivo, we created a conditional knockout of the Cul3 gene in mice. Interestingly, the biallelic loss of Cul3 in primary fibroblasts derived from these mice results in increased cyclin E expression and reduced cell viability, paralleling the loss of Cul3 protein expression. Cell cycle analysis of viable, Cul3 hypomorphic cells shows that decreasing the levels of Cul3 increases both cyclin E protein levels and the number of cells in S phase. In order to examine the role of Cul3 in an in vivo setting, we determined the effect of deletion of the Cul3 gene in liver. This gene deletion resulted in a dramatic increase in cyclin E levels as well as an increase in cell size and ploidy. The results we report here show that the constitutive degradation pathway for cyclin E that is regulated by the Cul3-based E3 ligase is essential to maintain quiescence in mammalian cells.

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