The ubiquitous nature of cancer: the role of the SCFFbw7 complex in development and transformation

Crusio, Kelly M.; King, Bryan; Reavie, Linsey B.; Aifantis, Iannis

doi:10.1038/onc.2010.222

Cited by 104 publications

(104 citation statements)

References 78 publications

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“…The deregulation of the UPS has been observed in many types of cancer, and studies targeting the UPS for cancer therapy are being conducted (27). As a component of the UPS, Fbw7 ubiquitin ligase plays a vital role in cell fate decisions (35,42). It was recently shown that Fbw7 controlled the fate of hematopoietic stem cells (43) and affected the proliferation and lymphomagenesis of mouse T cells (44), both through the regulation of c-Myc expression.…”

Section: Discussionmentioning

confidence: 99%

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Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

Huang

Weng

Wang

et al. 2012

Molecular Cancer Therapeutics

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The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitinproteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

“…It was previously shown that the GSK-3-mediated phosphorylation of c-Myc T58 was needed for the efficient binding of c-Myc by Fbw7 (34,35). We investigated GSK-3 activity in K562 cells upon oridonin treatment.…”

Section: Oridonin Activates Gsk-3 and Enhances The Phosphorylation Ofmentioning

confidence: 99%

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

Huang

Weng

Wang

et al. 2012

Molecular Cancer Therapeutics

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“…The loss and mutation of this gene is frequently detected in various types of cancers (Mao et al, 2004;Perez-Losada et al, 2005;Tan et al, 2008;Crusio et al, 2010). To address whether downregulation of Fbxw7 mimicked the effects from increase of miR-27a expression, we introduced specific siRNAs duplex targeting Fbxw7 into HBER cells.…”

Section: The Fbxw7 Gene Is a Direct Target Of Mir-27amentioning

confidence: 99%

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

Wang

et al. 2011

Oncogene

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“…The regulation of KLF2 mRNA expression has been well studied in the endothelium [16]. Accumulating evidence shows that MEF2 transcription factors are the central regulators of KLF2 mRNA expression in endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Wang

Liu

et al. 2013

Cell Res

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F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCF FBW7 (a complex of SKP1, cullin-1 and FBW7), plays important roles in various physiological and pathological processes. Although FBW7 is required for vascular development, its function in the endothelium remains to be investigated. In this study, we show that FBW7 is an important regulator of endothelial functions, including angiogenesis, leukocyte adhesion and the endothelial barrier integrity. Using RNA interference, we found that the depletion of FBW7 markedly impairs angiogenesis in vitro and in vivo. We identified the zinc finger transcription factor Krüppel-like factor 2 (KLF2) as a physiological target of FBW7 in endothelial cells. Knockdown of FBW7 expression resulted in the accumulation of endogenous KLF2 protein in endothelial cells. FBW7-mediated KLF2 destruction was shown to depend on the phosphorylation of KLF2 via glycogen synthase kinase-3 (GSK3) at two conserved phosphodegrons. Mutating these phosphodegron motifs abolished the FBW7-mediated degradation and ubiquitination of KLF2. The siRNAmediated knockdown of FBW7 showed that KLF2 is an essential target of FBW7 in the regulation of endothelial functions. Moreover, FBW7-mediated KLF2 degradation was shown to be critical for angiogenesis in teratomas and in zebrafish development. Taken together, our study suggests a role for FBW7 in the processes of endothelial cell migration, angiogenesis, inflammation and barrier integrity, and provides novel insights into the regulation of KLF2 stability in vivo.

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The ubiquitous nature of cancer: the role of the SCFFbw7 complex in development and transformation

Cited by 104 publications

References 78 publications

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

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