SKP1

Gene Summary

Gene:SKP1; S-phase kinase associated protein 1
Aliases: OCP2, p19A, EMC19, SKP1A, OCP-II, TCEB1L
Location:5q31.1
Summary:This gene encodes a component of SCF complexes, which are composed of this protein, cullin 1, a ring-box protein, and one member of the F-box family of proteins. This protein binds directly to the F-box motif found in F-box proteins. SCF complexes are involved in the regulated ubiquitination of specific protein substrates, which targets them for degradation by the proteosome. Specific F-box proteins recognize different target protein(s), and many specific SCF substrates have been identified including regulators of cell cycle progression and development. Studies have also characterized the protein as an RNA polymerase II elongation factor. Alternative splicing of this gene results in two transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:S-phase kinase-associated protein 1
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SKP1 (cancer-related)

Mertins P, Mani DR, Ruggles KV, et al.
Proteogenomics connects somatic mutations to signalling in breast cancer.
Nature. 2016; 534(7605):55-62 [PubMed] Free Access to Full Article Related Publications
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.

Yang Y, Lu Y, Wang L, et al.
Skp2 is associated with paclitaxel resistance in prostate cancer cells.
Oncol Rep. 2016; 36(1):559-66 [PubMed] Related Publications
Prostate cancer is the most commonly diagnosed tumor in men in the United States. Patients with hormone-refractory prostate cancer are often treated with paclitaxel, but most of them eventually develop drug resistance. S-phase kinase associated protein 2 (Skp2) is a component of the SCF (Skp1-Cullin1-F-box) type of E3 ubiquitin ligase complexes. In the present study, we investigated the role of Skp2 in paclitaxel-resistant DU145-TxR or PC-3-TxR cells by Skp2 silencing or using Skp2 inhibitors. We first confirmed that Skp2 expression is up-regulated in DU145-TxR or PC-3-TxR cells compared with their parental cells DU145 or PC-3, respectively. Knockdown of Skp2 or Skp2 inhibitor treatment in DU145-TxR or PC-3-TxR cells restored paclitaxel sensitivity. E-cadherin was decreased while Vimentin was increased in PC-3-TxR or DU145-TxR cells. In addition, p27 expression was inversely correlated with Skp2 expression in DU145-TxR or PC-3-TxR cells. Moreover, p27 was found to increase in both Skp2 silencing PC-3-TxR and DU145-TxR cells. These results suggest that Skp2 is associated with prostate cancer cell resistance to paclitaxel. Skp2 may be a potential therapeutic target for drug-resistant prostate cancer.

Kim SH, Ho JN, Jin H, et al.
Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines.
Investig Clin Urol. 2016; 57(1):63-72 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The mechanism of resistance to cisplatin during treatment of bladder cancer (BC) has been a subject of intense investigation in clinical research. This study aims to identify candidate genes associated with resistance to cisplatin, in order to understand the resistance mechanism of BC cells to the drug, by combining the use of microarray profiling, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses.
MATERIALS AND METHODS: The cisplatin sensitive human BC cell line (T24) and the cisplatin resistant BC cell line, T24R2, were used for microarray analysis to determine the differential expression of genes that are significant in cisplatin resistance. Candidate upregulated genes belonging to three well-known cancer-related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (p53 tumor suppressor, apoptosis, and cell cycle) were selected from the microarray data. These candidate genes, differentially expressed in T24 and T24R2, were then confirmed by quantitative RT-PCR and western blot. A fold change ≥2 with a p-value <0.05 was considered significant.
RESULTS: A total of 18 significantly upregulated genes were detected in the three selected cancer-related pathways in both microarray and RT-PCR analyses. These genes were PRKAR2A, PRKAR2B, CYCS, BCL2, BIRC3, DFFB, CASP6, CDK6, CCNE1, STEAP3, MCM7, ORC2, ORC5, ANAPC1, and ANAPC7, CDC7, CDC27, and SKP1. Western blot analyses also confirmed the upregulation of BCL2, MCM7, and CCNE1 at the protein level, indicating their crucial association with cisplatin resistance.
CONCLUSIONS: The BCL2, MCM7, and CCNE1 genes might play distinctive roles in cisplatin resistance in BC.

Zheng N, Wang Z, Wei W
Ubiquitination-mediated degradation of cell cycle-related proteins by F-box proteins.
Int J Biochem Cell Biol. 2016; 73:99-110 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
F-box proteins, subunits of SKP1-cullin 1-F-box protein (SCF) type of E3 ubiquitin ligase complexes, have been validated to play a crucial role in governing various cellular processes such as cell cycle, cell proliferation, apoptosis, migration, invasion and metastasis. Recently, a wealth of evidence has emerged that F-box proteins is critically involved in tumorigenesis in part through governing the ubiquitination and subsequent degradation of cell cycle proteins, and dysregulation of this process leads to aberrant cell cycle progression and ultimately, tumorigenesis. Therefore, in this review, we describe the critical role of F-box proteins in the timely regulation of cell cycle. Moreover, we discuss how F-box proteins involve in tumorigenesis via targeting cell cycle-related proteins using biochemistry studies, engineered mouse models, and pathological gene alternations. We conclude that inhibitors of F-box proteins could have promising therapeutic potentials in part through controlling of aberrant cell cycle progression for cancer therapies.

Wu WJ, Shi J, Hu G, et al.
Wnt/β-catenin signaling inhibits FBXW7 expression by upregulation of microRNA-770 in hepatocellular carcinoma.
Tumour Biol. 2016; 37(5):6045-51 [PubMed] Related Publications
FBXW7 (F-box and WD repeat domain-containing 7) is the F-box protein component of a Skp1-Cul1-F-box protein-type (SCF-type) ubiquitin ligase. Previous studies have shown that FBXW7 serves as a tumor suppressor and is frequently downregulated in many types of human neoplasms. However, the molecular mechanisms for its downregulation remain poorly understood. Hyperactivation of Wnt/β-catenin signaling pathway is viewed as crucial for tumorigenesis, including hepatocellular carcinoma (HCC). In the present study, we show that protein levels, but not message RNA, of FBXW7 were suppressed by Wnt3a treatment or transfection of a constitutively activated β-catenin in HCC cells. Besides, microRNA-770 was identified as an important downstream target of Wnt/β-catenin signaling, to inhibit FBXW7 expression through targeting its 3'-untranslated region. Thus, our results suggest a previously unknown Wnt/β catenin-miR-770-FBXW7 molecular network in the HCC development.

Kitagawa K, Kitagawa M
The SCF-type E3 Ubiquitin Ligases as Cancer Targets.
Curr Cancer Drug Targets. 2016; 16(2):119-29 [PubMed] Related Publications
The ubiquitin system controls protein stability and function. F-box proteins form SCF (SKP1-Cullin1-F-box protein)-type ubiquitin (E3) ligases to selectively target their substrates for degradation via the ubiquitin-proteasome pathway. Here, we review F-box proteins associated with cancer development. S-phase kinase-associated protein 2 (SKP2) (also known as FBXL1) is often overexpressed in human cancers, and functions as an oncogenic E3 ligase to degrade tumor suppressor gene products. Moreover, F-box/WD repeat-containing protein 7 (FBXW7) (also known as Fbw7) is often mutated in human cancers and functions as a tumor suppressive E3 ligase targeting oncogenic proteins for degradation. SKP2 is a potential drug target for cancer therapy and FBXW7 is useful in determining patient diagnosis, prognosis, and drug sensitivity. In this review, we also discuss other F-box proteins involved in cancer-associated cellular processes such as cell cycle control, epigenetic regulation, epithelial mesenchymal transition, apoptosis/survival, drug resistance, and DNA-damage responses.

Wu ZH, Pfeffer LM
MicroRNA regulation of F-box proteins and its role in cancer.
Semin Cancer Biol. 2016; 36:80-7 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
MicroRNAs (miRNAs) are small endogenous non-coding RNAs, which play critical roles in cancer development by suppressing gene expression at the post-transcriptional level. In general, oncogenic miRNAs are upregulated in cancer, while miRNAs that act as tumor suppressors are downregulated, leading to decreased expression of tumor suppressors and upregulated oncogene expression, respectively. F-box proteins function as the substrate-recognition components of the SKP1-CUL1-F-box (SCF)-ubiquitin ligase complex for the degradation of their protein targets by the ubiquitin-proteasome system. Therefore F-box proteins and miRNAs both negatively regulate target gene expression post-transcriptionally. Since each miRNA is capable of fine-tuning the expression of multiple target genes, multiple F-box proteins may be suppressed by the same miRNA. Meanwhile, one F-box proteins could be regulated by several miRNAs in different cancer types. In this review, we will focus on miRNA-mediated downregulation of various F-box proteins, the resulting stabilization of F-box protein substrates and the impact of these processes on human malignancies. We provide insight into how the miRNA: F-box protein axis may regulate cancer progression and metastasis. We also consider the broader role of F-box proteins in the regulation of pathways that are independent of the ubiquitin ligase complex and how that impacts on oncogenesis. The area of miRNAs and the F-box proteins that they regulate in cancer is an emerging field and will inform new strategies in cancer treatment.

Heo J, Eki R, Abbas T
Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis.
Semin Cancer Biol. 2016; 36:33-51 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
F-box proteins are substrate receptors of the SCF (SKP1-Cullin 1-F-box protein) E3 ubiquitin ligase that play important roles in a number of physiological processes and activities. Through their ability to assemble distinct E3 ubiquitin ligases and target key regulators of cellular activities for ubiquitylation and degradation, this versatile group of proteins is able to regulate the abundance of cellular proteins whose deregulated expression or activity contributes to disease. In this review, we describe the important roles of select F-box proteins in regulating cellular activities, the perturbation of which contributes to the initiation and progression of a number of human malignancies.

Randle SJ, Laman H
F-box protein interactions with the hallmark pathways in cancer.
Semin Cancer Biol. 2016; 36:3-17 [PubMed] Related Publications
F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.

Uddin S, Bhat AA, Krishnankutty R, et al.
Involvement of F-BOX proteins in progression and development of human malignancies.
Semin Cancer Biol. 2016; 36:18-32 [PubMed] Related Publications
The Ubiquitin Proteasome System (UPS) is a core regulator with various protein components (ubiquitin-activating E1 enzymes, ubiquitin-conjugating E2 enzymes, ubiquitin-protein E3 ligases, and the 26S proteasome) which work together in a coordinated fashion to ensure the appropriate and efficient proteolysis of target substrates. E3 ubiquitin ligases are essential components of the UPS machinery, working with E1 and E2 enzymes to bind substrates and assist the transport of ubiquitin molecules onto the target protein. As the UPS controls the degradation of several oncogenes and tumor suppressors, dysregulation of this pathway leads to several human malignancies. A major category of E3 Ub ligases, the SCF (Skp-Cullin-F-box) complex, is composed of four principal components: Skp1, Cul1/Cdc53, Roc1/Rbx1/Hrt1, and an F-box protein (FBP). FBPs are the substrate recognition components of SCF complexes and function as adaptors that bring substrates into physical proximity with the rest of the SCF. Besides acting as a component of SCF complexes, FBPs are involved in DNA replication, transcription, cell differentiation and cell death. This review will highlight the recent literature on three well characterized FBPs SKP2, Fbw7, and beta-TRCP. In particular, we will focus on the involvement of these deregulated FBPs in the progression and development of various human cancers. We will also highlight some novel substrates recently identified for these FBPs.

Jiang ZH, Dong XW, Shen YC, et al.
DNA damage regulates ARID1A stability via SCF ubiquitin ligase in gastric cancer cells.
Eur Rev Med Pharmacol Sci. 2015; 19(17):3194-200 [PubMed] Related Publications
OBJECTIVE: The gene product of the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) is a member of the SWI/SNF adenosine triphosphate-dependent chromatin-remodeling complexes, which plays an essential role in controlling gene expression and is also involved in cancer development. ARID1A is frequently mutated in a wild variety of cancers and function as a tumor suppressor in several kinds of cancers. ARID1A was down-regulated in gastric cancer, and associated poor patient prognosis. However, how ARID1A protein is regulated in gastric cancer remains largely unknown.
MATERIALS AND METHODS: Here, we show that ARID1A protein is rapidly ubiquitinated and degradated in gastric cancer cells in response to DNA damage treatment.
RESULTS: Using genetic and pharmacologic Cullin inactivation coupled with in vitro ubiquitination assay, we demonstrate that ARID1A is a substrate of the Cullin-SKP1-F-box protein (SCF) complexes. Moreover, gastric cancer cells with forced expression of ARID1A showed an increased sensitivity to DNA damage reagents. Thus, our data uncovered a previous unknown posttranscriptional regulation of ARID1A by SCF E3 ligase in gastric cancer cells in DNA damage response.
CONCLUSIONS: These findings suggest ARID1A might be a promising drug target in gastric cancer treatment.

Tebay LE, Robertson H, Durant ST, et al.
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease.
Free Radic Biol Med. 2015; 88(Pt B):108-46 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and stress-inducible expression of a battery of genes encoding key components of the glutathione-based and thioredoxin-based antioxidant systems, as well as aldo-keto reductase, glutathione S-transferase, and
NAD(P)H: quinone oxidoreductase-1 drug-metabolizing isoenzymes along with multidrug-resistance-associated efflux pumps. It therefore plays a pivotal role in both intrinsic resistance and cellular adaptation to reactive oxygen species (ROS) and xenobiotics. Activation of Nrf2 can, however, serve as a double-edged sword because some of the genes it induces may contribute to chemical carcinogenesis by promoting futile redox cycling of polycyclic aromatic hydrocarbon metabolites or confer resistance to chemotherapeutic drugs by increasing the expression of efflux pumps, suggesting its cytoprotective effects will vary in a context-specific fashion. In addition to cytoprotection, Nrf2 also controls genes involved in intermediary metabolism, positively regulating those involved in NADPH generation, purine biosynthesis, and the β-oxidation of fatty acids, while suppressing those involved in lipogenesis and gluconeogenesis. Nrf2 is subject to regulation at multiple levels. Its ability to orchestrate adaptation to oxidants and electrophiles is due principally to stress-stimulated modification of thiols within one of its repressors, the Kelch-like ECH-associated protein 1 (Keap1), which is present in the cullin-3 RING ubiquitin ligase (CRL) complex CRLKeap1. Thus modification of Cys residues in Keap1 blocks CRLKeap1 activity, allowing newly translated Nrf2 to accumulate rapidly and induce its target genes. The ability of Keap1 to repress Nrf2 can be attenuated by p62/sequestosome-1 in a mechanistic target of rapamycin complex 1 (mTORC1)-dependent manner, thereby allowing refeeding after fasting to increase Nrf2-target gene expression. In parallel with repression by Keap1, Nrf2 is also repressed by β-transducin repeat-containing protein (β-TrCP), present in the Skp1-cullin-1-F-box protein (SCF) ubiquitin ligase complex SCFβ-TrCP. The ability of SCFβ-TrCP to suppress Nrf2 activity is itself enhanced by prior phosphorylation of the transcription factor by glycogen synthase kinase-3 (GSK-3) through formation of a DSGIS-containing phosphodegron. However, formation of the phosphodegron in Nrf2 by GSK-3 is inhibited by stimuli that activate protein kinase B (PKB)/Akt. In particular, PKB/Akt activity can be increased by phosphoinositide 3-kinase and mTORC2, thereby providing an explanation of why antioxidant-responsive element-driven genes are induced by growth factors and nutrients. Thus Nrf2 activity is tightly controlled via CRLKeap1 and SCFβ-TrCP by oxidative stress and energy-based signals, allowing it to mediate adaptive responses that restore redox homeostasis and modulate intermediary metabolism. Based on the fact that Nrf2 influences multiple biochemical pathways in both positive and negative ways, it is likely its dose-response curve, in terms of susceptibility to certain degenerative disease, is U-shaped. Specifically, too little Nrf2 activity will lead to loss of cytoprotection, diminished antioxidant capacity, and lowered β-oxidation of fatty acids, while conversely also exhibiting heightened sensitivity to ROS-based signaling that involves receptor tyrosine kinases and apoptosis signal-regulating kinase-1. By contrast, too much Nrf2 activity disturbs the homeostatic balance in favor of reduction, and so may have deleterious consequences including overproduction of reduced glutathione and NADPH, the blunting of ROS-based signal transduction, epithelial cell hyperplasia, and failure of certain cell types to differentiate correctly. We discuss the basis of a putative U-shaped Nrf2 dose-response curve in terms of potentially competing processes relevant to different stages of tumorigenesis.

Bochis OV, Irimie A, Pichler M, Berindan-Neagoe I
The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer.
J Gastrointestin Liver Dis. 2015; 24(2):225-34 [PubMed] Related Publications
Colorectal cancer is one of the most frequent cancers worldwide, having the fourth mortality rate among cancers in both sexes. Numerous studies are investigating the signalling pathways and different factors involved in the development and progression of colorectal cancer. It has recently been shown that the S-phase kinase-associated protein 2 (Skp2) overexpression plays an important role in the pathogenesis of colorectal cancer. We review the role of Skp2 and its ubiquitin-proteasome pathway in colorectal cancer. The F-box protein Skp2, a component of the SCF (Skp1-Cullin 1-F-box) E3 ubiquitin-ligase complex, has been shown to regulate cellular proliferation, cancer progression and metastasis by targeting several cell cycle regulators for ubiquitination and subsequent 26S proteasome degradation. The best known protein substrate of the Skp2 is the cyclin-dependent kinase inhibitor 1B (CDKN1B), also known as p27Kip1. Overexpression of Skp2 and loss of CDKN1B (p27) was strongly associated with aggressive tumor behavior and poor clinical outcome in a variety of cancers, including colorectal cancer. An efficient interaction between Skp2 and CDKN1B (p27) requires the presence of an essential activator of the SCF-Skp2 complex, the cyclin-dependent kinase subunit 1 (Cks1) cofactor. Alterations in the Skp2, Cks1 and CDKN1B (p27) expression have major effects on colorectal carcinogenesis and may serve as an important and independent prognostic marker. Furthermore, we highlight that Skp2 may be a promising therapeutic target for colorectal cancer, and development of Skp2 inhibitors would have a great impact on colorectal cancer therapy.

Wang H, Pan JQ, Luo L, et al.
NF-κB induces miR-148a to sustain TGF-β/Smad signaling activation in glioblastoma.
Mol Cancer. 2015; 14:2 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Inflammatory cytokines and transforming growth factor-β (TGF-β) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-β signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-β signaling.
METHODS: We determined NF-κB and TGF-β/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase-associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice.
RESULTS: QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-β/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-β/Smad signaling in a cohort of human glioblastoma specimens.
CONCLUSIONS: These findings uncover a plausible mechanism for NF-κB-sustained TGF-β/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer.

Yan R, He L, Li Z, et al.
SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer.
Genes Dev. 2015; 29(6):672-85 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention.

Sun XX, He X, Yin L, et al.
The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc.
Proc Natl Acad Sci U S A. 2015; 112(12):3734-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
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.

Yang CH, Pfeffer SR, Sims M, et al.
The oncogenic microRNA-21 inhibits the tumor suppressive activity of FBXO11 to promote tumorigenesis.
J Biol Chem. 2015; 290(10):6037-46 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The microRNA miR-21 is overexpressed in most human cancers and accumulating evidence indicates that it functions as an oncogene. Since miRNAs suppress the expression of their target genes, we hypothesized that some miR-21 targets may act as tumor suppressors, and thus their expression would be anticipated to be reduced by the high miR-21 levels observed in various human cancers. By microarray analysis and quantitative PCR we identified and validated FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) as a miR-21 target gene. FBXO11 is a component of the SKP1-CUL1-F-box ubiquitin ligase complex that targets proteins for ubiquitination and proteosomal degradation. By loss of function and gain of function studies, we show that FBXO11 acts as a tumor suppressor, promotes apoptosis and mediates the degradation of the oncogenic protein BCL6. The critical role that FBXO11 plays in miR-21-mediated tumorigenesis was demonstrated by a rescue experiment, in which silencing FBXO11 in miR-21KD cancer cells restored their high tumorigenicity. Expression of miR-21 and FBXO11 are inversely correlated in tumor tissue, and their expression correlates with patient survival and tumor grade. High FBXO11 expression correlates with better patient survival and lower tumor grade consistent with its tumor suppressor activity. In contrast high miR-21 expression, which correlates with poor patient survival and higher tumor grade, is consistent with its oncogenic activity. Our results identify FBXO11 as a novel miR-21 target gene, and demonstrate that the oncogenic miRNA miR-21 decreases the expression of FBXO11, which normally acts as a tumor suppressor, and thereby promotes tumorigenesis.

Baumann U, Fernández-Sáiz V, Rudelius M, et al.
Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.
Nat Med. 2014; 20(12):1401-9 [PubMed] Related Publications
We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.

Xu H, Choe C, Shin SH, et al.
Silencing of KIF14 interferes with cell cycle progression and cytokinesis by blocking the p27(Kip1) ubiquitination pathway in hepatocellular carcinoma.
Exp Mol Med. 2014; 46:e97 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Although it has been suggested that kinesin family member 14 (KIF14) has oncogenic potential in various cancers, including hepatocellular carcinoma (HCC), the molecular mechanism of this potential remains unknown. We aimed to elucidate the role of KIF14 in hepatocarcinogenesis by knocking down KIF14 in HCC cells that overexpressed KIF14. After KIF14 knockdown, changes in tumor cell growth, cell cycle and cytokinesis were examined. We also examined cell cycle regulatory molecules and upstream Skp1/Cul1/F-box (SCF) complex molecules. Knockdown of KIF14 resulted in suppression of cell proliferation and failure of cytokinesis, whereas KIF14 overexpression increased cell proliferation. In KIF14-silenced cells, the levels of cyclins E1, D1 and B1 were profoundly decreased compared with control cells. Of the cyclin-dependent kinase inhibitors, the p27(Kip1) protein level specifically increased after KIF14 knockdown. The increase in p27(Kip1) was not due to elevation of its mRNA level, but was due to inhibition of the proteasome-dependent degradation pathway. To explore the pathway upstream of this event, we measured the levels of SCF complex molecules, including Skp1, Skp2, Cul1, Roc1 and Cks1. The levels of Skp2 and its cofactor Cks1 decreased in the KIF14 knockdown cells where p27(Kip1) accumulated. Overexpression of Skp2 in the KIF14 knockdown cells attenuated the failure of cytokinesis. On the basis of these results, we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1, which target p27(Kip1) for degradation by the 26S proteasome, leading to accumulation of p27(Kip1). The downregulation of Skp2 and Cks1 also resulted in cytokinesis failure, which may inhibit tumor growth. To the best of our knowledge, this is the first report that has identified the molecular target and oncogenic effect of KIF14 in HCC.

Dong S, Zhao J, Wei J, et al.
F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation.
Mol Cancer. 2014; 13:76 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.
METHODS: FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining.
RESULTS: Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype.
CONCLUSIONS: Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis.

Wang Z, Liu P, Inuzuka H, Wei W
Roles of F-box proteins in cancer.
Nat Rev Cancer. 2014; 14(4):233-47 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
F-box proteins, which are the substrate-recognition subunits of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.

Xie C, Powell C, Yao M, et al.
Ubiquitin-conjugating enzyme E2C: a potential cancer biomarker.
Int J Biochem Cell Biol. 2014; 47:113-7 [PubMed] Related Publications
The ubiquitin-conjugating enzymes 2C (UBE2C) is an integral component of the ubiquitin proteasome system. UBE2C consists of a conserved core domain containing the catalytic Cys residue and an N-terminal extension. The core domain is required for ubiquitin adduct formation by interacting with the ubiquitin-fold domain in the E1 enzyme, and contributes to the E3 enzyme binding. UBE2C N-terminal extension regulates E3 enzyme activity as a part of an intrinsic inhibitory mechanism. UBE2C is required for the destruction of mitotic cyclins and securin, which are essential for spindle assembly checkpoint and mitotic exit. The UBE2C mRNA and/or protein levels are aberrantly increased in many cancer types with poor clinical outcomes. Accumulation of UBE2C stimulates cell proliferation and anchorage-independent growth. UBE2C transgenic mice are prone to develop spontaneous tumors and carcinogen-induced tumor with evidence of chromosome aneuploidy.

Migita K, Takayama T, Matsumoto S, et al.
Prognostic impact of RING box protein-1 (RBX1) expression in gastric cancer.
Gastric Cancer. 2014; 17(4):601-9 [PubMed] Related Publications
BACKGROUND: RING box protein-1 (RBX1) is an essential component of the E3 ubiquitin ligase Skp1/Cullin/RBX1/F-box protein complex. Although an altered expression of RBX1 has been reported in several human cancers, the role of RBX1 in gastric cancer remains unknown.
METHODS: We investigated the RBX1 expression in primary gastric cancer tissues from 145 patients by immunohistochemistry, and explored its clinical relevance and prognostic value. Furthermore, the effect of RBX1 expression on cancer cell proliferation was analyzed in vitro using a siRNA silencing technique.
RESULTS: The RBX1 expression was abundant in gastric cancer tissues. There was a significant difference in the expression level of RBX1 in terms of the tumor depth (P = 0.008), presence of distant metastasis (P = 0.016) and venous invasion (P = 0.005). The postoperative overall (P < 0.001) and relapse-free survival (P < 0.001) rates were significantly poorer in patients with RBX1-high tumors than in patients with RBX1-low tumors. There was a significant correlation of the RBX1 status with postoperative hematogenous recurrence (P = 0.013). Importantly, the RBX1 status was identified as an independent prognostic factor for gastric cancer (P = 0.002). Furthermore, RBX1 gene silencing significantly inhibited the proliferation of gastric cancer cells in vitro.
CONCLUSIONS: The RBX1 expression has a significant prognostic value in gastric cancer. RBX1 might play an important role in regulating the proliferation of gastric cancer cells and promoting the development of postoperative recurrence. Our data provide a rationale for developing a novel therapy targeting RBX1 for gastric cancer.

Tan X, Wu Q, Cai Y, et al.
Novel association between CD74 polymorphisms and hematologic toxicity in patients with NSCLC after platinum-based chemotherapy.
Clin Lung Cancer. 2014; 15(1):67-78.e12 [PubMed] Related Publications
BACKGROUND: Platinum-based chemotherapy regimens can cause DNA damage. Macrophage migration inhibitory factor (MIF) plays an important role in the regulation of the cell cycle by either controlling the activity of the SKP1-Cullin/Cdc53-F-box protein ubiquitin ligase (SCF) complex or activating its receptor, CD74.
PATIENTS AND METHODS: We used a pathway-based approach to investigate the association between genetic polymorphisms in MIF-pathway genes and the outcomes of platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). We used iSelect 24×1 HD BeadChip (Illumina, Inc, San Diego, CA) to genotype 32 tag and potentially functional single nucleotide polymorphisms (SNPs) of 8 selected genes and evaluated their associations with different outcomes for 1004 patients with advanced NSCLC treated with platinum-based chemotherapy. In particular, gastrointestinal toxicity and hematologic toxicity were analyzed for associations with specific genotypes, alleles, and haplotypes.
RESULTS: Two polymorphisms of CD74, rs2748249 (C/A) and rs1560661 (A/G), were significantly associated with hematologic toxicity. Carrying an A allele in rs2748249 was associated with higher hematologic toxicity (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.24-2.39; P = .001) and carrying a G allele in rs1560661 was associated with lower hematologic toxicity (OR, 0.42; 95% CI, 0.25-0.70; P = .00099) compared with the wild type. Haplotype analysis revealed that the patients with the CG haplotype (consisting of rs2748249 and rs1560661) had reduced hematologic toxicity compared with patients with other haplotypes (OR, 0.70; 95% CI, 0.56-0.87; P = .0013). The binding domain shared by 3 transcription factors (activator protein-2α [AP-2α], progesterone response A/B, and TFII-I) comprised the 2 SNPs that may be involved in the regulation of CD74-related B-cell survival.
CONCLUSION: Our study is the first to suggest, to our knowledge, that polymorphisms in CD74 might be a marker of lower hematologic toxicity for patients with advanced NSCLC receiving platinum-based chemotherapy.

Achiwa Y, Hasegawa K, Udagawa Y
Effect of ursolic acid on MAPK in cyclin D1 signaling and RING-type E3 ligase (SCF E3s) in two endometrial cancer cell lines.
Nutr Cancer. 2013; 65(7):1026-33 [PubMed] Related Publications
Cyclin D1 regulates G1 progression and is important in the development and proliferation of various human cancers. Cyclin D1 gene expression is activated by the Ras kinase cascade. Nuclear cyclin D1 levels are dependent on cytoplasmic degradation of cyclin D1 via ubiquitin-mediated proteolysis. We sought to determine whether the important MAPK signaling pathway, in the cyclin D1 cascade, including FBXW8, Cullin1, and the ubiquitination pathway mediated these effects. Ursolic acid (UA) treatment of SNG-2 cells, an endometrial cancer cell line, decreased cyclin D1, pERK1/2, FBXW8, and Cullin1 levels in a dose- and time-dependent manner. RING-type E3 ligase consists of CulIin1, Rbx, Skp1, and a member of the F-box protein family. In SNG-2, both dose- and time-dependent inhibition of Rbx 1 were observed following treatment with UA. Moreover, in HEC108 cells, another endometrial cancer cell line, UA treatment decreased cyclin D1, pERK1/2, and Cullin1 levels in a dose- and time-dependent manner and UA markedly inhibited FBXW8. Treatment of HEC108 cells moderately decreased Rbx1 in a dose- and-time-dependent fashion. In contrast, UA treatment increased ubiquitinated proteins in a dose- and time-dependent manner in both cell lines. RING-type E3 ligase accumulated in the cytoplasm following UA treatment of SNG-2cells. That in turn prevented cytoplasmic degradation of cyclin D1 via RING-type E3 (SCF E3s) ligase. In conclusion, our study found inhibition of the MAPK- cyclin D1 pathway and RING type E3 ligase (SCF E3s) in both endometrial cancer cell lines. Furthermore, CD36 was noted as a cell surface receptor for UA.

Cepeda D, Ng HF, Sharifi HR, et al.
CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer.
EMBO Mol Med. 2013; 5(7):1067-86 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCF(FBXO28) activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCF(FBXO28) plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer.

Lockwood WW, Chandel SK, Stewart GL, et al.
The novel ubiquitin ligase complex, SCF(Fbxw4), interacts with the COP9 signalosome in an F-box dependent manner, is mutated, lost and under-expressed in human cancers.
PLoS One. 2013; 8(5):e63610 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under-expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non-small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes.

Wang W, Qiu J, Liu Z, et al.
Overexpression of RING box protein-1 (RBX1) associated with poor prognosis of non-muscle-invasive bladder transitional cell carcinoma.
J Surg Oncol. 2013; 107(7):758-61 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: RING box protein-1 (RBX1) is a key subunit of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex. Altered expression RBX1 is shown to associate with tumorigenesis and tumor progression. This study detected RBX1 expression for association with clinical significance (such as clinicopathological data and survival of the patients) in non-muscle-invasive bladder transitional cell carcinoma (NMIBC).
METHODS: A total of 70 primary NMIBC tissue specimens and 24 normal tissue specimens were recruited and analyzed immunohistochemically for expression of RBX1 protein and associated with clinicopathological data and survival of the patients.
RESULTS: RBX1 was highly expressed in NMIBC, but was lowly expressed in the normal tissue. RBX1 expression was associated with high tumor grade and advanced clinical stage (P < 0.01 and P < 0.05, respectively). Moreover, patients with high RBX1 expression had shorter recurrence-free survival and progression-free survival rates (P < 0.001 and P < 0.01, respectively). Multivariate analysis demonstrated that RBX1 expression is an independent prognostic factor for tumor recurrence and progression of NMIBC (P < 0.05).
CONCLUSIONS: Overexpression of RBX1 protein contributes to tumor progression and poor prognosis of NMIBC.

Xie CM, Wei W, Sun Y
Role of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases in skin cancer.
J Genet Genomics. 2013; 40(3):97-106 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis and degradation of key regulatory proteins. While protein synthesis can be regulated at multiple levels, protein degradation is mainly controlled by the ubiquitin-proteasome system (UPS), which consists of two distinct steps: (1) ubiquitylation of targeted protein by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and (2) subsequent degradation by the 26S proteasome. Among all E3 ubiquitin ligases, the SCF (SKP1-CUL1-F-box protein) E3 ligases are the largest family and are responsible for the turnover of many key regulatory proteins. Aberrant regulation of SCF E3 ligases is associated with various human diseases, such as cancers, including skin cancer. In this review, we provide a comprehensive overview of all currently published data to define a promoting role of SCF E3 ligases in the development of skin cancer. The future directions in this area of research are also discussed with an ultimate goal to develop small molecule inhibitors of SCF E3 ligases as a novel approach for the treatment of human skin cancer. Furthermore, altered components or substrates of SCF E3 ligases may also be developed as the biomarkers for early diagnosis or predicting prognosis.

Katayama K, Noguchi K, Sugimoto Y
FBXO15 regulates P-glycoprotein/ABCB1 expression through the ubiquitin--proteasome pathway in cancer cells.
Cancer Sci. 2013; 104(6):694-702 [PubMed] Related Publications
Expression of P-glycoprotein (P-gp)/ABCB1 on cancer cell surfaces is a critical determinant of anticancer drug resistance. Regulators of P-gp expression and function are key molecules controlling drug resistance. Here we report the mechanism underlying the ubiquitin-proteasome pathway-mediated degradation of P-gp. The proteasome inhibitor MG132 increased the P-gp level, enhanced its ubiquitination, and delayed the disappearance of the ubiquitinated P-gp. To search for regulators of P-gp ubiquitination, MALDI-time of flight mass spectrometry analyses were carried out, and 22 candidates were identified as P-gp binding partners. Among them, FBXO15/Fbx15 is known as an F-box protein in the ubiquitin E3 ligase complex, Skp1-Cullin1-FBXO15 (SCF(Fbx15) ); therefore, we further studied the involvement of FBXO15 on P-gp degradation. Coprecipitation assays revealed that FBXO15 bound to P-gp. We screened ubiquitin-conjugating enzyme E2s that bind to FBXO15 and P-gp; Ube2r1/Cdc34/Ubc3 was found to be a binding partner. Exogenous FBXO15 expression enhanced P-gp ubiquitination, but FBXO15 knockdown suppressed it. FBXO15 knockdown increased P-gp expression without affecting its mRNA level. Ube2r1 knockdown decreased P-gp ubiquitination, and simultaneous knockdown of Ube2r1 with FBXO15 further suppressed the ubiquitination. Ube2r1 knockdown increased P-gp expression, suggesting that Ube2r1 is a partner of FBXO15 in P-gp ubiquitination. FBXO15 knockdown enhanced vincristine resistance and lowered intracellular levels of rhodamine 123. These data suggest that FBXO15 and Ube2r1 regulate P-gp expression through the ubiquitin-proteasome pathway.

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