Fbw7α and Fbw7γ Collaborate To Shuttle Cyclin E1 into the Nucleolus for Multiubiquitylation

Bhaskaran, Nimesh; Drogen, Frank van; Ng, Hwee-Fang; Kumar, Raman; Ekholm-Reed, Susanna; Peter, Matthias; Sangfelt, Olle; Reed, Steven I.

doi:10.1128/mcb.00288-12

Cited by 32 publications

(33 citation statements)

References 41 publications

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“…However, how c-Myc stability is controlled by the Fbw7 isoforms in specific cell compartments under physiological conditions is still not clear. Recently, it has been shown that Fbw7α and Fbw7γ function sequentially to regulate the turnover of cyclin E, another Fbw7 analog substrate, instead of targeting cyclin E independently in their respective compartments (31,32). Fbw7α promotes initial isomerization of cyclin E by PIN1 without ubiquitinating cyclin E, possibly coupled with nucleolar translocation, and allows successive ubiquitination of cyclin E by Fbw7γ in the nucleolus (31,32).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that Fbw7α and Fbw7γ function sequentially to regulate the turnover of cyclin E, another Fbw7 analog substrate, instead of targeting cyclin E independently in their respective compartments (31,32). Fbw7α promotes initial isomerization of cyclin E by PIN1 without ubiquitinating cyclin E, possibly coupled with nucleolar translocation, and allows successive ubiquitination of cyclin E by Fbw7γ in the nucleolus (31,32). Thus, it will be interesting in future studies to examine whether Fbw7α may also promote isomerization of c-Myc by PIN1 that facilitates c-Myc translocation into the nucleolus, where it is polyubiquitinated by Fbw7γ.…”

Section: Discussionmentioning

confidence: 99%

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The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc

Sun

Yin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

176

199

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c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCF Fbw7 (a SKP1-cullin-1-F-box complex that contains the F-box and WD repeat domain-containing 7, Fbw7, as the F-box protein) and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) 28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ but not the nucleoplasmic Fbw7α. However, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc's nucleolar degradation pathway.c-Myc | USP36 | ubiquitination | deubiquitination | nucleolus

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc

Sun

Yin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

176

199

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“…Despite their different subcellular localization, all of them have been shown to be able to degrade nuclear proteins [49]. Moreover, a recent study provides an interesting model that FBW7α and γ collaborate to target cyclin E for ubiquitination in the nucleolus in a Pin1-mediated isomerization-dependent manner [50]. KLF2 is a transcriptional factor that is mainly localized in the nucleoplasm.…”

Section: Discussionmentioning

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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“…On the other hand, it may be that the relevant function of FBXW7 is SREBPindependent. FBXW7 is expressed as three isoforms, with FBXW7α and FBXW7γ regulating cyclin E degradation in the nucleus (27), whereas cytoplasmic FBXW7β promotes the degradation of the mitochondrial prosurvival factor Mcl-1 (21). In response to oxidative stress, Parkin targets the proteasomal degradation of FBXW7β to allow Mcl-1 stabilization and promote neuron survival.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Ivatt

Sánchez-Martínez

Godena

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

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Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), Fbox and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis. P arkinson disease (PD) is an age-related neurodegenerative disease caused principally by the loss of midbrain dopaminergic neurons, resulting in motor disturbances, such as postural instability, resting tremor, and bradykinesia, as well as other nonmotor symptoms. Current therapeutic strategies alleviate symptoms by the replacement of dopamine, with variable efficacy and substantial side effects. However, there are currently no established curative, preventative, or disease-modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Genetic analyses have identified causative mutations for autosomal dominant and recessive forms of familial parkinsonism. Functional studies of these genes have provided great insight into potential pathogenic mechanisms of inherited forms of PD; however, it is unclear how these may relate to the more common sporadic forms of PD. To gain insight into the genetic influence in sporadic PD, genome-wide association studies (GWASs) have revealed several loci that are significantly associated with the occurrence of PD, and so are considered potential risk factors. However, we lack mechanistic insight into how many of the associated risk loci may contribute to pathogenesis.Mitochondrial dysfunction has long been considered a key contributing factor in the pathogenesis of PD, with evidence from postmortem tissue, epidemiological studies, and genetics. In particular, a body of evidence indicates that two genes linked to recessive parkinsonism, PTEN-induced kinase 1 (PINK1) and parkin, act in a common pathway to regulate mitochondrial turnover, providing an attractive hypothesis for the impact of mitochondrial homeostasis on pathogenesis (1). The process of mitophagy to degrade dysfunctional mitochondria has been extensively studied using uncoupling agents to dissipate the mitochondrial membrane potential (ΔΨm) (2). Following loss of ΔΨm, PINK1 accumulates on the outer mit...

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Fbw7α and Fbw7γ Collaborate To Shuttle Cyclin E1 into the Nucleolus for Multiubiquitylation

Cited by 32 publications

References 41 publications

The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc

The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

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