Mind the Gap between the Endothelium and E3 Ubiquitin Ligase: TRIM21 Is a Viable Therapeutic Target in Sepsis-induced Endothelial Dysfunction

Abstractβ-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.

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TRIP13 promotes the cell proliferation, migration and invasion of glioblastoma through the FBXW7/c-MYC axis

British Journal of Cancer ◽

10.1038/s41416-019-0633-0 ◽

2019 ◽

Vol 121 (12) ◽

pp. 1069-1078 ◽

Cited By ~ 5

Author(s):

Guanghui Zhang ◽

Qingzong Zhu ◽

Gang Fu ◽

Jianbing Hou ◽

Xiaosong Hu ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Therapeutic Target ◽

Biological Effect ◽

Thyroid Hormone Receptor ◽

E3 Ubiquitin Ligase ◽

Mitotic Checkpoint ◽

Migration And Invasion ◽

Cell Models ◽

Aaa Atpase

Abstract Background Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important role in the mitotic checkpoint. TRIP13 is highly expressed in various human tumours and promotes tumorigenesis. However, the biological effect of TRIP13 in GBM cells remains unclear. Methods We generated GBM cell models with overexpressed or silenced TRIP13 via lentivirus-mediated overexpression and RNAi methods. The biological role of TRIP13 in the proliferation, migration and invasion of GBM cells has been further explored. Results Our research indicated that TRIP13 was highly expressed in GBM tissues and cells. We found that the proliferation, migration and invasion abilities were inhibited in TRIP13-knockdown GBM cells. These results indicated that TRIP13 plays an important role in the tumorigenesis of GBM. Moreover, we found that TRIP13 first stabilised c-MYC by inhibiting the transcription of FBXW7, which is an E3 ubiquitin ligase of c-MYC, by directly binding to the promoter region of FBXW7. Therefore, our study indicated that the TRIP13/FBXW7/c-MYC pathway might provide a prospective therapeutic target in the treatment of GBM. Conclusions These results indicated that TRIP13 plays an oncogenic role in GBM. The TRIP13/FBXW7/c-MYC pathway might act as a prospective therapeutic target for GBM patients.

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The E3 ubiquitin ligase seven in absentia homolog 1 may be a potential new therapeutic target for Parkinson′s disease

Neural Regeneration Research ◽

10.4103/1673-5374.162763 ◽

2015 ◽

Vol 10 (8) ◽

pp. 1286 ◽

Cited By ~ 6

Author(s):

Zeng-lin Cai ◽

Jing Xu ◽

Shou-ru Xue ◽

Yuan-yuan Liu ◽

Yong-jin Zhang ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Therapeutic Target ◽

E3 Ubiquitin Ligase ◽

Seven In Absentia

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miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

International Journal of Molecular Sciences ◽

10.3390/ijms21010355 ◽

2020 ◽

Vol 21 (1) ◽

pp. 355 ◽

Cited By ~ 2

Author(s):

Anthea Di Rita ◽

Teresa Maiorino ◽

Krenare Bruqi ◽

Floriana Volpicelli ◽

Gian Carlo Bellenchi ◽

...

Keyword(s):

Protein Content ◽

Ubiquitin Ligase ◽

Therapeutic Target ◽

Feedback Loop ◽

E3 Ubiquitin Ligase ◽

Human Diseases ◽

Mrna Levels ◽

Cellular Homeostasis ◽

Promising Therapeutic Target ◽

Selective Elimination

The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.

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Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3

Journal of Translational Medicine ◽

10.1186/s12967-021-03069-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qingsong Jin ◽

Liangyan Lin ◽

Tiantian Zhao ◽

Xiaoyan Yao ◽

Yaqin Teng ◽

...

Keyword(s):

Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Ubiquitin Ligase ◽

Umbilical Vein ◽

E3 Ubiquitin Ligase ◽

Rat Tissues ◽

No Production ◽

Common Chronic Disease

Abstract Background Diabetes mellitus (DM), a most common chronic disease, is featured with impaired endothelial function and bioavailability of nitric oxide (NO), while E3 ubiquitin ligase appears to alleviate endothelial dysfunction as a promising option for DM treatment. Herein, we aimed to determine whether E3 ubiquitin ligase casitas B-lineage lymphoma (Cbl) alleviates endothelial dysfunction in DM rats by JAK2/STAT4 pathway. Methods A rat model of DM was developed through intraperitoneal injection of streptozotocin, followed by collection of aortic tissues to determine the expression of Cbl, JAK2, runt-related transcription factor 3 (Runx3) and STAT4. Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose (HG) condition to induce DM as an in vitro model. With gain- and loss-function method, we assessed the aberrantly expressed Cb1 on endothelial dysfunction, NO production and apoptosis of HUVECs. Results Cbl was reduced in DM rat tissues and HG-induced HUVECs, where JAK2, Runx3 and STAT4 were elevated. It was found that overexpression of Cbl alleviated endothelial dysfunction by increasing NO production and restoring vasodilation and suppressing apoptosis of HUVECs. Mechanistically, Cb1 enhanced JAK2 ubiquitination and decreased JAK2 and STAT4 expression, where STAT4 improved Runx3 expression by regulating histone H3 lysine 4 trimethylation level. Overexpression of JAK2 and STAT4, or Runx3 increased apoptosis of HUVECs, abrogating the effect of Cb1 on endothelial function. Conclusion In conclusion, Cbl alleviates endothelial dysfunction by inactivation of the JAK2/STAT4 pathway and inhibition of Runx3 expression in DM. These evidence might underlie novel Cbl-based treatment against DM in the future.

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