The ubiquitin-proteasome pathway regulates lysosomal degradation of the growth hormone receptor and its ligand

2001 ◽  
Vol 29 (4) ◽  
pp. 488-493 ◽  
Author(s):  
P. van Kerkhof ◽  
G. J. Strous
Keyword(s):  
Growth Hormone ◽  
Proteasome Inhibitor ◽  
Growth Hormone Receptor ◽  
Proteasome Inhibitors ◽  
Plasma Membrane Protein ◽  
Lysosomal Degradation ◽  
Ubiquitin Proteasome Pathway ◽  
Gh Receptor ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The growth hormone (GH) receptor (GHR) is a mammalian plasma membrane protein whose internalization is mediated by the ubiquitin-proteasome pathway. GH internalization and degradation are inhibited when cells are treated with proteasome inhibitors. Here we show that a GHR truncated at residue 369 can enter the cells in the presence of a proteasome inhibitor, but that the subsequent lysosomal degradation of GH is blocked. Lysosomal inhibitors prolong the half-life of both receptor and ligand. Experiments with antibodies against different receptor tail sections show that degradation of the GHR cytosolic domain precedes degradation of the extracellular GH-binding domain. A possible role for the ubiquitin-proteasome pathway in the degradation of the receptor and ligand is discussed.

Lysosomal degradation of the growth hormone receptor is regulated by the ubiquitin-proteasome pathway

2001 ◽  
Vol 29 (3) ◽  
pp. A64-A64
Author(s):  
P. van Kerkhof ◽  
C. M. Alves dos Santos ◽  
M. Sachse ◽  
J. Klumperman ◽  
G. Bu ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Lysosomal Degradation ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The Ubiquitin-Proteasome Pathway and Resistance Mechanisms Developed Against the Proteasomal Inhibitors in Cancer Cells

2020 ◽  
Vol 21 (13) ◽  
pp. 1313-1325
Author(s):  
Azmi Yerlikaya ◽  
Ertan Kanbur
Keyword(s):  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Pressure ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Background: The ubiquitin-proteasome pathway is crucial for all cellular processes and is, therefore, a critical target for the investigation and development of novel strategies for cancer treatment. In addition, approximately 30% of newly synthesized proteins never attain their final conformations due to translational errors or defects in post-translational modifications; therefore, they are also rapidly eliminated by the ubiquitin-proteasome pathway. Objective: Here, an effort was made to outline the recent findings deciphering the new molecular mechanisms involved in the regulation of ubiquitin-proteasome pathway as well as the resistance mechanisms developed against proteasome inhibitors in cell culture experiments and in the clinical trials. Results: Since cancer cells have higher proliferation rates and are more prone to translational errors, they require the ubiquitin-proteasome pathway for selective advantage and sustained proliferation. Therefore, drugs targeting the ubiquitin-proteasome pathway are promising agents for the treatment of both hematological and solid cancers. Conclusions: A number of proteasome inhibitors are approved and used for the treatment of advanced and relapsed multiple myeloma. Unfortunately, drug resistance mechanisms may develop very fast within days of the start of the proteasome inhibitor-treatment either due to the inherent or acquired resistance mechanisms under selective drug pressure. However, a comprehensive understanding of the mechanisms leading to the proteasome inhibitor-resistance will eventually help the design and development of novel strategies involving new drugs and/or drug combinations for the treatment of a number of cancers.

Abstract 37: Centrosome Destabilization Through the Ubiquitin-Proteasome Pathway Regulates Proplatelet Production

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kellie R Machlus ◽  
Prakrith Vijey ◽  
Thomas Soussou ◽  
Joseph E Italiano
Keyword(s):  
Protein Degradation ◽  
Proteasome Inhibitors ◽  
Aurora Kinase ◽  
Proteasome Activity ◽  
Major Pathway ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Proplatelet Formation

Background: Proteasome inhibitors such as bortezomib, a chemotherapeutic used to treat multiple myeloma, induce thrombocytopenia within days of initiation. The mechanism for this thrombocytopenia has been tied to data revealing that proteasome activity is essential for platelet formation. The major pathway of selective protein degradation uses ubiquitin as a marker that targets proteins for proteolysis by the proteasome. This pathway is previously unexplored in megakaryocytes (MKs). Objectives: We aim to define the mechanism by which the ubiquitin-proteasome pathway affects MK maturation and platelet production. Results: Pharmacologic inhibition of proteasome activity blocks proplatelet formation in megakaryocytes. To further characterize how this degradation was occurring, we probed distinct ubiquitin pathways. Inhibition of the ubiquitin-activating enzyme E1 significantly inhibited proplatelet formation up to 73%. In addition, inhibition of the deubiquitinase proteins UCHL5 and USP14 significantly inhibited proplatelet formation up to 83%. These data suggest that an intact ubiquitin pathway is necessary for proplatelet formation. Proteomic and polysome analyses of MKs undergoing proplatelet formation revealed a subset of proteins decreased in proplatelet-producing megakaryocytes, consistent with data showing that protein degradation is necessary for proplatelet formation. Specifically, the centrosome stabilizing proteins Aurora kinase (Aurk) A/B, Tpx2, Cdk1, and Plk1 were decreased in proplatelet-producing MKs. Furthermore, inhibition of AurkA and Plk1, but not Cdk1, significantly inhibited proplatelet formation in vitro over 83%. Conclusions: We hypothesize that proplatelet formation is triggered by centrosome destabilization and disassembly, and that the ubiquitin-proteasome pathway plays a crucial role in this transformation. Specifically, regulation of the AurkA/Plk1/Tpx2 pathway may be key in centrosome integrity and initiation of proplatelet formation. Determination of the mechanism by which the ubiquitin-proteasome pathway regulates the centrosome and facilitates proplatelet formation will allow us to design better strategies to target and reverse thrombocytopenia.

The Ubiquitin Proteasome Pathway from Bench to Bedside

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 220-225 ◽  
Author(s):  
Robert Z. Orlowski
Keyword(s):  
Phase I ◽  
Hematological Malignancies ◽  
Expression Profiles ◽  
Proteasome Inhibitors ◽  
Rational Approach ◽  
Significant Activity ◽  
Ubiquitin Proteasome Pathway ◽  
Gene And Protein Expression ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The validation of the ubiquitin-proteasome pathway as a target for therapy of hematological malignancies stands out as one salient example of the ability to translate laboratory-based findings from the bench to the bedside. Preclinical studies showed that proteasome inhibitors had significant activity against models of non-Hodgkin lymphoma and multiple myeloma, and identified some of the relevant mechanisms of action. These led to phase I through III trials of the first clinically available proteasome inhibitor, bortezomib, which confirmed its activity as a single agent in these diseases. Modulation of proteasome function was then found to be a rational approach to achieve both chemosensitization in vitro and in vivo, as well as to overcome chemotherapy resistance. Based on these findings, first-generation bortezomib-based regimens incorporating traditional chemotherapeutics such as alkylating agents, anthracyclines, immunomodulatory agents, or steroids have been evaluated, and many show promise of enhanced clinical anti-tumor efficacy. Further studies of the pro-and anti-apoptotic actions of proteasome inhibitors, and of their effects on gene and protein expression profiles, suggest that novel agents, such as those targeting the heat shock protein pathways, are exciting candidates for incorporation into these combinations. Phase I trials to test these concepts are just beginning, but have already shown some encouraging results. Finally, novel proteasome inhibitors are being developed with unique properties that may also have therapeutic applications. Taken together, these studies demonstrate the power of rational drug design and development to provide novel, effective therapies for patients with hematological malignancies.

scholarly journals The Proteasome Inhibitor, MG132, Attenuates Diabetic Nephropathy by Inhibiting SnoN DegradationIn VivoandIn Vitro

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Wei Huang ◽  
Chen Yang ◽  
Qinling Nan ◽  
Chenlin Gao ◽  
Hong Feng ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Proteasome Inhibitor ◽  
Kidney Damage ◽  
Control Group ◽  
Glomerular Mesangial Cells ◽  
Proteasome Inhibitor Mg132 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Transforming growth factor-β(TGF-β) has been shown to be involved in diabetic nephropathy (DN). The SnoN protein can regulate TGF-βsignaling through interaction with Smad proteins. Recent studies have shown that SnoN is mainly degraded by the ubiquitin-proteasome pathway. However, the role of SnoN in the regulation of TGF-β/Smad signaling in DN is still unclear. In this study, diabetic rats were randomly divided into a diabetic control group (DC group) and a proteasome inhibitor (MG132) diabetes therapy group (DT group). Kidney damage parameters and the expression of SnoN, Smurf2, and TGF-βwere observed. Simultaneously, we cultured rat glomerular mesangial cells (GMCs) stimulated with high glucose, and SnoN and Arkadia expression were measured. Results demonstrated that 24-hour urine protein, ACR, BUN, and the expression of Smurf2 and TGF-βwere significantly increased (P<0.05), whereas SnoN was significantly decreased in the DC group (P<0.05). However, these changes diminished after treatment with MG132. SnoN expression in GMCs decreased significantly (P<0.05), but Arkadia expression gradually increased due to high glucose stimulation (P<0.05), which could be almost completely reversed by MG132 (P<0.05). The present results support the hypothesis that MG132 may alleviate kidney damage by inhibiting SnoN degradation and TGF-βactivation, suggesting that the ubiquitin-proteasome pathway may become a new therapeutic target for DN.

scholarly journals Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shansa Pranami E. Jayaweera ◽  
Sacheela Prasadi Wanigasinghe Kanakanamge ◽  
Dharshika Rajalingam ◽  
Gayathri N. Silva
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Biochemical Properties ◽  
Regulatory Proteins ◽  
Toxicity Profile ◽  
The Us ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.

scholarly journals Proteasome Inhibitors Block a Late Step in Lysosomal Transport of Selected Membrane but not Soluble Proteins

2001 ◽  
Vol 12 (8) ◽  
pp. 2556-2566 ◽  
Author(s):  
Peter van Kerkhof ◽  
Cristina M. Alves dos Santos ◽  
Martin Sachse ◽  
Judith Klumperman ◽  
Guojun Bu ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Proteasome Inhibitors ◽  
Endocytic Pathway ◽  
Endosomal Sorting ◽  
Ubiquitin Proteasome Pathway ◽  
Late Step ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Lysosomal Transport

The ubiquitin-proteasome pathway acts as a regulator of the endocytosis of selected membrane proteins. Recent evidence suggests that it may also function in the intracellular trafficking of membrane proteins. In this study, several models were used to address the role of the ubiquitin-proteasome pathway in sorting of internalized proteins to the lysosome. We found that lysosomal degradation of ligands, which remain bound to their receptors within the endocytic pathway, is blocked in the presence of specific proteasome inhibitors. In contrast, a ligand that dissociates from its receptor upon endosome acidification is degraded under the same conditions. Quantitative electron microscopy showed that neither the uptake nor the overall distribution of the endocytic marker bovine serum albumin-gold is substantially altered in the presence of a proteasome inhibitor. The data suggest that the ubiquitin-proteasome pathway is involved in an endosomal sorting step of selected membrane proteins to lysosomes, thereby providing a mechanism for regulated degradation.

Regulation of elastin gene transcription by proteasome dysfunction

2005 ◽  
Vol 289 (3) ◽  
pp. C766-C773 ◽  
Author(s):  
Ping-Ping Kuang ◽  
Ronald H. Goldstein
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Proteasome Inhibitors ◽  
Lung Fibroblasts ◽  
Extracellular Matrix Protein ◽  
Mrna Levels ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Elastin Gene

Elastin, a major extracellular matrix protein and the core component of elastic fiber, is essential to maintain lung structural integrity and normal physiological function. We previously found that the downregulation of elastin gene transcription by IL-1β is mediated via activation of NF-κB and CCAAT/enhancer binding protein (C/EBP)β, both targets of the ubiquitin-proteasome pathway. To further investigate the molecular mechanisms that underlie the control of elastin gene expression, we disrupted the ubiquitin-proteasome pathway with specific proteasome inhibitors. We found that specific proteasome inhibitors decreased the steady-state level of elastin mRNA in a dose-responsive manner. Run-on assay and promoter reporter study indicated that the proteasome inhibitor MG-132 repressed the rate of elastin transcription. MG-132 did not affect mRNA levels of NF-κB and C/EBPβ, or the nuclear presence of NF-κB, but markedly increased C/EBPβ isoforms, including liver-enriched transcriptional activating protein and liver-enriched transcriptional inhibitory protein. Addition of cycloheximide blocked these increases and the downregulation of elastin mRNA by MG-132. The MG-132-induced downregulation of elastin transcription was dependent on C/EBPβ expression as assessed with small interfering RNA. These results indicate that the ubiquitin-proteasome pathway plays an essential role in maintaining elastin gene expression in lung fibroblasts. Disruption of this pathway results in the downregulation of tropoelastin transcription via posttranscriptionally induced C/EBPβ isoforms.

scholarly journals The ubiquitin-proteasome pathway and proteasome inhibitors

2001 ◽  
Vol 21 (4) ◽  
pp. 245-273 ◽  
Author(s):  
Jayhyuk Myung ◽  
Kyung Bo Kim ◽  
Craig M. Crews
Keyword(s):  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway
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