FBXW7 is involved in Aurora B degradation

Teng, Chieh Lin Jerry; Hsieh, Yun Chi; Phan, Liem; Shin, Ji‐Hyun; Gully, Christopher; Velázquez-Torres, Guermarie; Skerl, Stephen; Yeung, Sai Ching Jim; Hsu, Shih-Kuang; Lee, Mong Hong

doi:10.4161/cc.22381

Cited by 44 publications

(47 citation statements)

References 44 publications

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“…Previous studies have proved that FBW7 can regulate several cell cycle‐associated proteins, such as kinase Aurora B and cyclin E 8, 21. In light of determining the regulating effect of FBW7 on cell division of glioma, FC analysis was applied.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, many upstream molecules, such as transcriptional factors, kinases and microRNA, can also regulate FBW7 either transcriptionally or post‐translationally 24. For example, 1 study has reported that a p53‐FBW7‐Aurora B axis, which identified FBW7 as a transcriptional target of p53 21. Another study found that FBW7 could be phosphorylated and destabilized by ERK kinase 25.…”

Section: Discussionmentioning

confidence: 99%

“…Cell proliferation is tightly associated with the cell cycle, which is rigidly regulated by a series of kinases, among which Cyclin E and Aurora B are 2 important FBW7 substrates involved in the promotion of G1/S and G2/M transition, respectively 5, 8, 21. Previous studies have implicated the role of FBW7 in the regulation of cell proliferation in colon, breast and kidney cancers 7.…”

Section: Discussionmentioning

confidence: 99%

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FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

Lin¹,

Qiu

et al. 2018

Cancer Science

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F‐box and WD repeat domain‐containing 7 (FBW7) is a SCF‐type E3 ubiquitin ligase targeting a multitude of oncoproteins for degradation. Acting as one of the most important tumor suppressors, it is frequently inactivated in various tumors. In this study we aimed to evaluate the relationship of FBW7 with glioma pathology and prognosis, and examine its effect in glioma malignancies and temozolomide (TMZ)‐based therapy. Clinical tissues and TCGA database analysis revealed that FBW7 expression was correlated inversely with glioma histology and positively with patient survival time. Lentivirus transfection‐induced FBW7 overexpression significantly suppressed proliferation, invasion and migration of U251 and U373 cells, whereas knockdown of FBW7 by targeted shRNA promoted proliferation, invasion and migration of glioma cells. Most importantly, the expression level of FBW7 was found to affect the 50% inhibitory concentration (IC50) of U251 and the TMZ‐resistant variant. Combining TMZ with FBW7 overexpression notably increased the cytotoxicity compared to TMZ treatment alone, which was conversely attenuated by FBW7 knockdown. Moreover, flow cytometry (FC) analysis showed overexpression of FBW7, TMZ or the combination‐increased proportion of G2/M arrest and the apoptotic rate, whereas FBW7 inhibition reduced G2/M arrest and apoptosis in U251 cells. Finally, mechanistic study found that FBW7 overexpression downregulated Aurora B, Mcl1 and Notch1 levels in a time‐dependent pattern and this expressional suppression was independent of TMZ. These findings collectively demonstrate the critical role of FBW7 as a prognostic factor and a potential target to overcome chemoresistance of glioblastoma.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

Lin¹,

Qiu

et al. 2018

Cancer Science

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“…Previous reports have shown that the ubiquitin E3 ligase complex SCF(FBXW7) and SCF(FBXL2) could mediated Aurora B ubiquitination and degradation [11,12]. However, which E3 ligase is required for the degradation of Aurora B during apoptosis is still unclear.…”

Section: Fbxw7 Is Required For the Degradation Of Aurora B During Apomentioning

confidence: 97%

“…Recently studies found the protein level of Aurora B is strictly controlled during each stage of mitosis, primarily through ubiquitination-mediated degradation [10]. Moreover, several E3 ligase complexes including FBXW7 and FBXL2 were reported to be able to target Aurora B for destruction [11,12]. Although ubiquitination-mediated degradation of Aurora B has been studied, a detailed mechanistic regulatory pathway for Aurora B stability remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The Deubiquitinating Enzyme USP14 Regulates Leukemic Chemotherapy Drugs-Induced Cell Apoptosis by Suppressing Ubiquitination of Aurora Kinase B

Song¹,

Ma²,

Yang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aurora kinase B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Aurora B has been found to be amplified and overexpressed in several types of leukemia. The deubiquitinating enzyme USP14 is one of three proteasome-associated deubiquitinating enzymes and plays critical roles in diverse biological processes including cancer. However, whether USP14 has a role in leukemia cells remains elusive. Methods: Leukemic U937, NB4 and Jurkat cells were treated with diverse apoptosis-inducing drugs. The interaction between USP14 and Aurora B were determined by Western blot. The effect of USP14 in the regulation of Aurora B was detected by cycloheximide (CHX) and deubiquitination assays. FACS assay was used to determine the apoptosis ratio of cells after treatments. Results: We found that Aurora B was ubiquitinated and degraded during leukemic chemotherapy drugs-induced cell apoptosis. FBXW7 mediated Aurora B ubiquitination and degradation during chemotherapeutic drugsinduced apoptosis. USP14 associated with Aurora B and prevented Aurora B degradation. Functionally, overexpression of USP14 inhibits chemotherapeutic drugs-induced apoptosis in leukemia cells. On the contrary, administration of b-AP15, a specific inhibitor of USP14, significantly increased leukemia cells apoptosis in a dose-dependent manner. Conclusion: Thus, our data suggest that USP14 plays a novel critical role of in leukemia cells apoptosis through Aurora B stabilization and USP14 could be a potential therapeutic target for leukemia.

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Haploid genetic screens identify genetic vulnerabilities to microtubule‐targeting agents

et al. 2018

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The absence of biomarkers to accurately predict anticancer therapy response remains a major obstacle in clinical oncology. We applied a genome‐wide loss‐of‐function screening approach in human haploid cells to characterize genetic vulnerabilities to classical microtubule‐targeting agents. Using docetaxel and vinorelbine, two well‐established chemotherapeutic agents, we sought to identify genetic alterations sensitizing human HAP1 cells to these drugs. Despite the fact that both drugs act on microtubules, a set of distinct genes were identified whose disruption affects drug sensitivity. For docetaxel, this included a number of genes with a function in mitosis, while for vinorelbine we identified inactivation of FBXW7,RB1, and NF2, three frequently mutated tumor suppressor genes, as sensitizing factors. We validated these genes using independent knockout clones and confirmed FBXW7 as an important regulator of the mitotic spindle assembly. Upon FBXW7 depletion, vinorelbine treatment led to decreased survival of cells due to defective mitotic progression and subsequent mitotic catastrophe. We show that haploid insertional mutagenesis screens are a useful tool to study genetic vulnerabilities to classical chemotherapeutic drugs by identifying thus far unknown sensitivity factors. These results provide a rationale for investigating patient response to vinca alkaloid‐based anticancer treatment in relation to the mutational status of these three tumor suppressor genes, and could in the future lead to the establishment of novel predictive biomarkers or suggest new drug combinations based on molecular mechanisms of drug sensitivity.

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FBXW7 is involved in Aurora B degradation

Cited by 44 publications

References 44 publications

FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

The Deubiquitinating Enzyme USP14 Regulates Leukemic Chemotherapy Drugs-Induced Cell Apoptosis by Suppressing Ubiquitination of Aurora Kinase B

Haploid genetic screens identify genetic vulnerabilities to microtubule‐targeting agents

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