proteasome pathway
Recently Published Documents


TOTAL DOCUMENTS

930
(FIVE YEARS 126)

H-INDEX

98
(FIVE YEARS 6)

2022 ◽  
Author(s):  
Yushan Zhu ◽  
Qiangqiang Liu ◽  
Qian Luo ◽  
Jianyu Feng ◽  
Yanping Zhao ◽  
...  

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is dynamically regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted the competitive binding of SIAH2 with OTUD5 to DBC1, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin-proteasome pathway. Siah2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of Siah2/DBC1. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3577
Author(s):  
Maria S. Manola ◽  
Sentiljana Gumeni ◽  
Ioannis P. Trougakos

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk.


2021 ◽  
Author(s):  
Stefan Kotschi ◽  
Anna Jung ◽  
Nienke Willemsen ◽  
Anahita Ofoghi ◽  
Bettina Proneth ◽  
...  

Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood. Here we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis. Our data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yinghui Wang ◽  
Yihang Xie ◽  
Boxuan Sun ◽  
Yuwei Guo ◽  
Ling Song ◽  
...  

Abstract Background Cervical cancers are closely associated with persistent high-risk human papillomaviruses (HR HPV) infection. The main mechanism involves the targeting of tumor suppressors, such as p53 and pRB, for degradation by HR HPV-encoded oncoproteins, thereby leading to tumorigenesis. Rap1GAP, a tumor suppressor gene, is down-regulated in many cancers. Previous studies have revealed that down-regulation of Rap1GAP is correlated with HPV16/18 infection in cervical cancer. However, the molecular mechanism remains unclear. In this study, we aimed to address the degradation pathway of Rap1GAP in HPV-positive cervical cancer cells. Methods HPV-positive (HeLa and SiHa) and negative (C33A) cervical cancer cells were used to analyze the pathways of Rap1GAP degradation. MG132 (carbobenzoxy-leucyl-leucyl-leucine) was used to inhibit protein degradation by proteasome. Co-immunoprecipitation (co-IP) was used to detect the interaction between Rap1GAP and E6AP. siRNA for E6AP was used to silence the expression of E6AP. Rapamycin was used to induce cell autophagy. Western blotting was used to check the levels of proteins. Results Following treatment with MG132, the levels of Rap1GAP were increased in the HR HPV-positive HeLa and SiHa cells, but not in the HPV-negative C33A cells. Co-immunoprecipitation assay revealed ubiquitinated Rap1GAP protein in HeLa and SiHa cells, but not in C33A cells. E6-associated protein (E6AP) mediated the ubiquitination of Rap1GAP by binding to it in HeLa and SiHa cells, but not in C33A cells. However, the levels of Rap1GAP were decreased in HeLa and SiHa cells after knocking down E6AP by siRNA. Silencing of E6AP did not affect the levels of Rap1GAP in C33A cells. Autophagy marker p62 was decreased and LC3 II/LC3 I was increased after knocking down E6AP in HeLa cells, but not in C33A cells. The levels of Rap1GAP were decreased after treating the cells with rapamycin to induce cell autophagy in HeLa and C33A cells. Conclusion Rap1GAP may be degraded by autophagy in cervical cancer cells, but HPV infection can switch the degradation pathway from autophagy to E6AP-mediated ubiquitin-proteasome degradation. E6AP may be a key component of the switch.


Agronomy ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2360
Author(s):  
Keheng Xu ◽  
Nan Wu ◽  
Wenbo Yao ◽  
Xiaowei Li ◽  
Yonggang Zhou ◽  
...  

The ubiquitin–proteasome pathway (UPP) is an important protein degradation pathway that can participate in the regulation of the physiological process of organisms by specifically removing abnormal peptides and degrading cell regulators. UPP mainly involves three enzymes, among which the E3 ubiquitin ligase function is central to UPP. E3 ubiquitin ligases can recruit substrate protein for ubiquitination, and they have various forms. Among them, the Skp1–Cul1–F-box (SCF) complex is the most representative member of the cullin RING ubiquitin ligases type in RING-domain E3 ligases, being mainly composed of Cullin 1, Skp1, Rbx1, and F-box proteins. The F-box protein is the key component for SCF to perform specific functions. The F-box protein is one of the largest protein families in plants, and its family members are involved in the regulation of many key physiological processes, such as growth and development of plants and the response to external stimuli. Herein, we briefly review the structure, classification, function, and hormone signaling pathways of F-box proteins.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yue Zhu ◽  
Huimin Ju ◽  
Hongyan Lu ◽  
Wei Tang ◽  
Junying Lu ◽  
...  

Abstract Background Bronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in premature infants, characterized by alveolar dysplasia and pulmonary microvascular remodeling. In the present study, we have investigated the functional roles of ubiquitin proteasome pathway (UPP) in BPD, and its relationship with endoplasmic reticulum stress (ERS) mediated type II alveolar epithelial cell (AECII) apoptosis. Methods A hyperoxia-induced BPD rat model was constructed and the pathologic changes of lung tissues were evaluated by hematoxylin–eosin staining. Cell apoptosis and protein expression were determined by TUNEL assay and Western blotting, respectively. Further reagent kit with specific fluorescent substrate was utilized to measure the activity of 20 s proteasome. Meanwhile, AECII were cultured in vitro and exposed to hyperoxia. AECII apoptosis were measured by flow cytometry. In contrast, MG132 treatment was induced to explore UPP during hyperoxia exposure on AECII apoptosis and ERS sensors expression. Results A significant increase in apoptosis and total ubiquitinated proteins expression were observed in BPD rats and AECII culture, and the change of UPP was associated with ERS. In order to confirm the role of UPP in AECII apoptosis of BPD, AECII cells were treated by MG132 with the concentration of 10 μmol/L under hyperoxia exposure. We found that the proteins expression of glucose-regulated protein 78 (GRP-78), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), as well as AECII apoptosis were increased following MG132 treatment. Furthermore, the relatively up-regulated in the levels of total ubiquitinated proteins expression and 20 s proteasome activity were correlated with increased ERS sensors expression. Conclusions Our findings indicate that UPP may participate in the ERS-induced AECII apoptosis under hyperoxia condition.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qi Zhang ◽  
Xinqi Zhang ◽  
Weiguo Dong

AbstractIt has been proved that TRAFs family proteins played malfunctioning roles in the development of human cancers. TRAF7 is the last one of TRAFs family proteins to be found, which was demonstrated to be involved in a serious of cancers development. In this study, we systematically investigated the molecular mechanisms of TRAF7 in facilitating hepatocellular carcinoma (HCC). We discovered that TRAF7 was overexpressed in tumor tissues and the increased TRAF7 expression was closely associated with tumor size, histologic grade, TNM stage and poor prognostication. TRAF7 overexpression repressed cell apoptosis and promoted cell proliferation, invasion and migration, whereas knockdown of TRAF7 in HCC cells had totally opposite effects. Besides, we identified the interaction between TRAF7 and P53 in HCC and demonstrated that TRAF7 promoted ubiquitin-proteasome mediated degradation of P53 at K48 site. The rescue assays further proved that the function of TRAF7 in inhibiting apoptosis and promoting tumor development was depended on P53 in HCC. Overall, this work identified that TARF7 promoted tumorigenesis by targeted degradation P53 for ubiquitin-mediated proteasome pathway. Targeting the TRAF7-P53 axis may provide new insights in the pathogenesis of HCC, and pave the way for developing novel strategies for HCC prevention and treatment.


2021 ◽  
Vol 11 ◽  
Author(s):  
Shansa Pranami E. Jayaweera ◽  
Sacheela Prasadi Wanigasinghe Kanakanamge ◽  
Dharshika Rajalingam ◽  
Gayathri N. Silva

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.


Sign in / Sign up

Export Citation Format

Share Document