更新于：2024-11-01

ubiquitin x FBW7

更新于：2024-11-01

基本信息

关联

项与 ubiquitin x FBW7 相关的药物

NM-20

靶点

FBW7 x ubiquitin

作用机制

FBW7调节剂 [+1]

在研机构-

原研机构

Neuromantis Pharmaceuticals, Inc.

在研适应症-

非在研适应症

帕金森病

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ubiquitin x FBW7 相关的临床结果

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100 项与 ubiquitin x FBW7 相关的转化医学

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0 项与 ubiquitin x FBW7 相关的专利（医药）

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126

项与 ubiquitin x FBW7 相关的文献（医药）

2024-09-04·GENETICS

Mck1-mediated proteolysis of CENP-A prevents mislocalization of CENP-A for chromosomal stability in Saccharomyces cerevisiae

Article

作者: Basrai, Munira A ; Zhang, Tianyi ; Au, Wei-Chun ; Kaiser, Peter ; Shrestha, Roshan L ; Ohkuni, Kentaro

AbstractCentromeric localization of evolutionarily conserved CENP-A (Cse4 in Saccharomyces cerevisiae) is essential for chromosomal stability. Mislocalization of overexpressed CENP-A to noncentromeric regions contributes to chromosomal instability in yeasts, flies, and humans. Overexpression and mislocalization of CENP-A observed in many cancers are associated with poor prognosis. Previous studies have shown that F-box proteins, Cdc4 and Met30 of the Skp, Cullin, F-box ubiquitin ligase cooperatively regulate proteolysis of Cse4 to prevent Cse4 mislocalization and chromosomal instability under normal physiological conditions. Mck1-mediated phosphorylation of Skp, Cullin, F-box-Cdc4 substrates such as Cdc6 and Rcn1 enhances the interaction of the substrates with Cdc4. Here, we report that Mck1 interacts with Cse4, and Mck1-mediated proteolysis of Cse4 prevents Cse4 mislocalization for chromosomal stability. Our results showed that mck1Δ strain overexpressing CSE4 (GAL-CSE4) exhibits lethality, defects in ubiquitin-mediated proteolysis of Cse4, mislocalization of Cse4, and reduced Cse4–Cdc4 interaction. Strain expressing GAL-cse4-3A with mutations in three potential Mck1 phosphorylation consensus sites (S10, S16, and T166) also exhibits growth defects, increased stability with mislocalization of Cse4-3A, chromosomal instability, and reduced interaction with Cdc4. Constitutive expression of histone H3 (Δ16H3) suppresses the chromosomal instability phenotype of GAL-cse4-3A strain, suggesting that the chromosomal instability phenotype is linked to Cse4-3A mislocalization. We conclude that Mck1 and its three potential phosphorylation sites on Cse4 promote Cse4–Cdc4 interaction and this contributes to ubiquitin-mediated proteolysis of Cse4 preventing its mislocalization and chromosomal instability. These studies advance our understanding of pathways that regulate cellular levels of CENP-A to prevent mislocalization of CENP-A in human cancers.

2024-04-01·Heliyon

Gkongensin A, an HSP90β inhibitor, improves hyperlipidemia, hepatic steatosis, and insulin resistance

Article

作者: Xue, Ning ; Miao, Kun ; Zhao, Yawei

The prevalence of obesity and its primary associated comorbidities, such as type 2 diabetes and fatty liver disease, has reached epidemic proportions, with no successful treatment available at present. Heat shock protein 90 (HSP90), a crucial chaperone, plays a key role in de novo lipogenesis (DNL) by stabilizing and maintaining sterol regulatory element binding protein (SREBP) activity. Kongensin A (KA), derived from Croton kongensis, inhibits RIP3-mediated necrosis, showing promise as an anti-necrotic and anti-inflammatory agent. It is not yet clear if KA, acting as an HSP90 inhibitor, can enhance hyperlipidemia, hepatic steatosis, and insulin resistance in obese individuals by controlling lipid metabolism. In this study, we first found that KA can potentially decrease lipid content at the cellular level. C57BL/6J mice were given a high-fat diet (HFD) and received KA and lovastatin through oral administration for 7 weeks. KA improved hyperlipidemia, fatty liver, and insulin resistance, as well as reduced body weight in diet-induced obese (DIO) mice, with no significant alteration in food intake. In vitro, KA suppressed DNL and reduced the amounts of mSREBPs. KA promoted mSREBP degradation via the FBW7-mediated ubiquitin-proteasome pathway. KA decreased the level of p-Akt Ser308, and p-GSK3β Ser9 by inhibiting the interaction between HSP90β and Akt. Overall, KA enhanced hyperlipidemia, hepatic steatosis, and insulin resistance by blocking SREBP activity, thereby impacting the FBW7-controlled ubiquitin-proteasome pathway.

2023-10-01·Hepatology

Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition

Article

作者: Li, Zenghui ; Wang, Chun-Hsiang ; Sun, Pei ; Wang, Sin-Tian ; Gao, Yating ; Chen, Tzu-Ying ; Duan, Shuangdi ; Gao, Qiang ; Shi, Liyang ; Qiu, Ye ; Young, Kung-Chia ; Li, Ya ; Liu, Lamei ; Pi, Jiayi ; Tang, Songqing ; Qin, Nong ; Sun, Hung-Yu

Background and Aims:Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis.Approach and Results:By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus.Conclusions:ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.