scholarly journals BAG2-Mediated Inhibition of CHIP Expression and Overexpression of MDM2 Contribute to the Initiation of Endometriosis by Modulating Estrogen Receptor Status

2021 ◽  
Vol 8 ◽  
Author(s):  
Li-Juan Chen ◽  
Bin Hu ◽  
Zhi-Qiang Han ◽  
Jian-Hua Zhu ◽  
Xu Fan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Molecular Mechanisms ◽  
Estrogenic Activity ◽  
Estrogen Receptor Status ◽  
Therapeutic Effects ◽  
Childbearing Age ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Endometriosis is an estrogen-dependent gynecological disease primarily affecting women of childbearing age, which gives rise to pelvic pain calling for multiple operations, and sometimes leading to infertility. However, the etiology of endometriosis remains poorly understood. In this study we investigated the roles of two Ubiquitin E3 Ligases, namely hsc70-interacting protein (CHIP) and mouse double minute 2 (MDM2), in the abnormal estrogenic activity in endometriosis. We first collected endometrial tissues from 91 cases of endometriosis and 78 cases of uterine myomas. Next, we established a murine endometriosis model by ectopic endometrial tissue implantation. In other studies, we isolated human endometrial stromal cells (HESCs) were isolated from the endometrial tissues, and performed HA- or FLAG-immunoprecipitation assays and immunoblotting with an anti-ubiquitin antibody to test the interactions among BAG2, CHIP, MDM2, estrogen receptor α (ERα), and ERβ. The expression of ERα was downregulated while that of ERβ, BAG2, and MDM2 was upregulated in human endometriosis and in the mouse model. CHIP degraded ERβ instead of ERα via the ubiquitin-proteasome pathway, while BAG2 impaired the CHIP-mediated degradation of ERβ in cultured HESCs derived from human endometriosis. The degradation of ERα by MDM2 in cultured endometriosis-HESCs also occurred through the ubiquitin-proteasome pathway. Knockdown of both BAG2 and MDM2 alleviated the development of endometriosis in mice. Our findings suggest that the interference of BAG2 and MDM2 may have therapeutic effects in endometriosis. Understanding better the molecular mechanisms underlying the regulation of the abnormal estrogenic activity in endometriosis is crucial for the advancement of targeted therapeutic strategies.

Molecular mechanisms of mammalian autophagy

2021 ◽  
Vol 478 (18) ◽  
pp. 3395-3421
Author(s):  
Charles B. Trelford ◽  
Gianni M. Di Guglielmo
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Molecular Pathways ◽  
Zymogen Granules ◽  
Ubiquitin Proteasome Pathway ◽  
Lysine Residues ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Functional Modulation ◽  
Chaperone Mediated Autophagy

The ubiquitin-proteasome pathway (UPP) and autophagy play integral roles in cellular homeostasis. As part of their normal life cycle, most proteins undergo ubiquitination for some form of redistribution, localization and/or functional modulation. However, ubiquitination is also important to the UPP and several autophagic processes. The UPP is initiated after specific lysine residues of short-lived, damaged or misfolded proteins are conjugated to ubiquitin, which targets these proteins to proteasomes. Autophagy is the endosomal/lysosomal-dependent degradation of organelles, invading microbes, zymogen granules and macromolecules such as protein, carbohydrates and lipids. Autophagy can be broadly separated into three distinct subtypes termed microautophagy, chaperone-mediated autophagy and macroautophagy. Although autophagy was once thought of as non-selective bulk degradation, advancements in the field have led to the discovery of several selective forms of autophagy. Here, we focus on the mechanisms of primary and selective mammalian autophagy pathways and highlight the current knowledge gaps in these molecular pathways.

scholarly journals The importance of ubiquitin E3 ligases, SCF and APC/C, in human cancers

2015 ◽  
Vol 88 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Ovidiu Vasile Bochis ◽  
Bogdan Fetica ◽  
Catalin Vlad ◽  
Patriciu Achimas-Cadariu ◽  
Alexandru Irimie
Keyword(s):  
Cell Cycle ◽  
Anaphase Promoting Complex ◽  
E3 Ligases ◽  
Cyclin Dependent Kinases ◽  
Ubiquitin Proteasome Pathway ◽  
Complex Process ◽  
Target Therapies ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein

     A normal evolution of the cell-cycle phases consists of multiple consecutive events, which makes it a highly complex process. Its preservation is regulated by Cyclin-Cdks (cyclin-dependent kinases) interactions and protein degradation, which is often controlled by the ubiquitin-mediated proteolysis.The goal of this review is to emphasize the most important features of the regulation of the cell-cycle involved in cancerogenesis, by presenting the involvement of E3 ubiquitin ligases SCF (Skp1-Cul1-F-box protein) and APC/C (Anaphase-promoting complex/cyclosome) in human malignancies. Also, we discuss the importance of the ubiquitin proteasome pathway blockade in cancer treatment. We know that a better understanding of the regulatory biology of the cell cycle can lead to the development of new target therapies for cancer.

scholarly journals The Role of Ubiquitin-Proteasome Pathway and Autophagy-Lysosome Pathway in Cerebral Ischemia

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Chunli Chen ◽  
Haiyun Qin ◽  
Jieqiong Tan ◽  
Zhiping Hu ◽  
Liuwang Zeng
Keyword(s):  
Cerebral Ischemia ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Current Knowledge ◽  
Pathological Process ◽  
Neuronal Necrosis ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Novel Therapeutic Strategies

The ubiquitin-proteasome pathway and autophagy-lysosome pathway are two major routes for clearance of aberrant cellular components to maintain protein homeostasis and normal cellular functions. Accumulating evidence shows that these two pathways are impaired during cerebral ischemia, which contributes to ischemic-induced neuronal necrosis and apoptosis. This review aims to critically discuss current knowledge and controversies on these two pathways in response to cerebral ischemic stress. We also discuss molecular mechanisms underlying the impairments of these protein degradation pathways and how such impairments lead to neuronal damage after cerebral ischemia. Further, we review the recent advance on the understanding of the involvement of these two pathways in the pathological process during many therapeutic approaches against cerebral ischemia. Despite recent advances, the exact role and molecular mechanisms of these two pathways following cerebral ischemia are complex and not completely understood, of which better understanding will provide avenues to develop novel therapeutic strategies for ischemic stroke.

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.

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.

scholarly journals Nonstructural Protein 5A Impairs DNA Damage Repair: Implications for Hepatitis C Virus-Mediated Hepatocarcinogenesis

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Tram T. T. Nguyen ◽  
Eun-Mee Park ◽  
Yun-Sook Lim ◽  
Soon B. Hwang
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
Viral Propagation ◽  
Ubiquitin Proteasome Pathway ◽  
Damage Repair ◽  
Ubiquitin Proteasome ◽  
Infected Cells ◽  
Proteasome Pathway ◽  
Insight Into

ABSTRACT RAD51-associated protein 1 (RAD51AP1) is a member of the multiprotein complexes postulated to carry out RAD51-mediated homologous recombination and DNA repair in mammalian cells. In the present study, we showed that hepatitis C virus (HCV) NS5A directly bound RAD51AP1 and increased the protein level of RAD51AP1 through modulation of the ubiquitin-proteasome pathway. We also demonstrated that RAD51AP1 protein levels were increased in the liver tissues of HCV-infected patients and NS5A-transgenic mice. Importantly, NS5A impaired DNA repair by disrupting the RAD51/RAD51AP1/UAF1 complex and rendered HCV-infected cells more sensitive to DNA damage. Silencing of RAD51AP1 expression resulted in a decrease of viral propagation. We further demonstrated that RAD51AP1 was involved in the assembly step of the HCV life cycle by protecting viral RNA. These data suggest that HCV exploits RAD51AP1 to promote viral propagation and thus that host DNA repair is compromised in HCV-infected cells. Overall, our findings provide mechanistic insight into the pathogenesis of HCV infection. IMPORTANCE Chronic infection with HCV is the leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCV-induced HCC are not fully understood. Here we demonstrate that the HCV NS5A protein physically interacts with RAD51AP1 and increases the RAD51AP1 protein level through modulation of the ubiquitin-proteasome pathway. HCV coopts host RAD51AP1 to protect viral RNA at an assembly step of the HCV life cycle. Note that the RAD51 protein accumulates in the cytoplasm of HCV-infected cells, and thus the RAD51/RAD51AP1/UAF1-mediated DNA damage repair system in the nucleus is compromised in HCV-infected cells. Our data may provide new insight into the molecular mechanisms of HCV-induced pathogenesis.

scholarly journals Inhibition of the Ubiquitin–Proteasome Pathway Does Not Protect against Ventilator-induced Accelerated Proteolysis or Atrophy in the Diaphragm

2014 ◽  
Vol 121 (1) ◽  
pp. 115-126 ◽  
Author(s):  
Ashley J. Smuder ◽  
W. Bradley Nelson ◽  
Matthew B. Hudson ◽  
Andreas N. Kavazis ◽  
Scott K. Powers
Keyword(s):  
Caspase 3 ◽  
Ring Finger ◽  
Diaphragm Muscle ◽  
Contractile Dysfunction ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Life Saving ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Fiber Atrophy

Abstract Background: Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin–proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. Methods: The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group). Results: The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx. Conclusion: Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.

scholarly journals Characterization of Arabidopsis thaliana R2R3 S23 MYB Transcription Factors as Novel Targets of the Ubiquitin Proteasome-Pathway and Regulators of Salt Stress and Abscisic Acid Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Chase Beathard ◽  
Sutton Mooney ◽  
Raed Al-Saharin ◽  
Aymeric Goyer ◽  
Hanjo Hellmann
Keyword(s):  
Transcription Factor ◽  
Abscisic Acid ◽  
Salt Stress ◽  
Abiotic Stress ◽  
Expression Patterns ◽  
26S Proteasome ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Rapid response to environmental changes and abiotic stress to coordinate developmental programs is critical for plants. To accomplish this, plants use the ubiquitin proteasome pathway as a flexible and efficient mechanism to control protein stability and to direct cellular reactions. Here, we show that all three members of the R2R3 S23 MYB transcription factor subfamily, MYB1, MYB25, and MYB109, are degraded by the 26S proteasome, likely facilitated by a CUL3-based E3 ligase that uses MATH-BTB/POZ proteins as substrate adaptors. A detailed description of MYB1, MYB25, and MYB109 expression shows their nuclear localization and specific tissue specific expression patterns. It further demonstrates that elevated expression of MYB25 reduces sensitivities toward abscisic acid, osmotic and salt stress in Arabidopsis, while downregulation of all S23 members results in hypersensitivities. Transcriptional profiling in root and shoot of seedlings overexpressing MYB25 shows that the transcription factor widely affects cellular stress pathways related to biotic and abiotic stress control. Overall, the work extends our knowledge on proteins targeted by CUL3-based E3 ligases that use MATH-BTB/POZ proteins as substrate adaptors and provides first information on all members of the MYB S23 subfamily.

Sign in / Sign up

Export Citation Format

Share Document