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FLASH GENE
Symbol FBXW7 contributors: mct/shn - updated : 13-04-2014
HGNC name F-box and WD repeat domain containing 7
HGNC id 16712
Location 4q31.3      Physical location : 153.242.410 - 153.456.172
Synonym name
  • F-box and WD-40 domain protein 7 (archipelago homolog, Drosophila)
  • F-box and WD-40 domain-containing protein 7
  • F-box protein FBW7
  • F-box protein FBX30
  • F-box protein SEL-10
  • F-box/WD repeat-containing protein 7
  • archipelago homolog
  • archipelago, Drosophila, homolog of
  • hAgo
  • hCdc4
  • homolog of C elegans sel-10
  • Synonym symbol(s) AGO, CDC4, DKFZp686F23254, FBW6, FBW7, FBX30, FBXO30, FBXW6, FLJ16457, SEL-10, SEL10
    DNA
    TYPE functioning gene
    STRUCTURE 213.76 kb     12 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure a 5' alternative exon
    MAPPING cloned Y linked N status tentative : very preliminary evidence
    Map cen - D4S1549 - D4S1548 - FBXW7 - D4S1588 - D4S2934 - qter
    Physical map
    MGC45428 4q31.23 hypothetical protein MGC45428 LRBA 4q31.22-q31.23 LPS-responsive vesicle trafficking, beach and anchor containing MAB21L2 4q31 mab-21-like 2 (C. elegans) LOC283341 4q31.23 similar to Adenylate kinase isoenzyme 4, mitochondrial (ATP-AMP transphosphorylase) RPS3A 4q31.2-q31.3 ribosomal protein S3A U73B 4q31.2-q31.3 RNA, U73B small nucleolar DKFZp434D0215 4q31.23 SH3 domain protein D19 LOC391704 4 similar to Prss32 protein ESSPL 4q31.23 epidermis-specific serine protease-like protein LOC391705 4 similar to RIKEN cDNA 9930021J17 PET112L 4q27-q28 PET112-like (yeast) LOC389232 4 LOC389232 LOC389233 4 LOC389233 FBXW7 4q31.23 F-box and WD-40 domain protein 7 (archipelago homolog, Drosophila) LOC391706 4 similar to ribosomal protein S3a; 40S ribosomal protein S3a; v-fos transformation effector protein 1 FLJ32028 4q31.3 hypothetical protein FLJ32028 TIGD4 4q31.23 tigger transposable element derived 4 ARFIP1 4q31.3 ADP-ribosylation factor interacting protein 1 (arfaptin 1) LOC152667 4q31.3 similar to NEFA-interacting nuclear protein NIP30 KIAA1727 4q31.3 KIAA1727 protein LOC389234 4 LOC389234 TRIM2 4q31.3 tripartite motif-containing 2 ANXA2P1 4q21-q31 annexin A2 pseudogene 1 GAJ 4q31.3 GAJ protein KIAA0922 4q31.23 GAJ protein LOC285532 4q31.3 similar to JM5 protein TLR2 4q32 toll-like receptor 2 LOC285533 4q31.3 hypothetical protein LOC285533 SFRP2 4q31.3 secreted frizzled-related protein 2 FLJ20047 4q31.3 hypothetical protein FLJ20047 LOC389235 4 similar to protocadherin 16 precursor; fibroblast cadherin FIB1; fibroblast cadherin 1; dachsous homologue PLRG1 4q31.2-q32.1 pleiotropic regulator 1 (PRL1homolog, Arabidopsis) FGB 4q28 fibrinogen, B beta polypeptide FGA 4q28 fibrinogen, A alpha polypeptide FGG 4q28 fibrinogen, G gamma polypeptide LRAT 4q31.1-q31.23 lecithin retinol acyltransferase (phosphatidylcholine--retinol O-acyltransferase) MGC27016 4q31.3 hypothetical protein MGC27016 LOC389236 4 LOC389236
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 splicing initiation site 3896 79.5 707 nucleoplasmic 2012 2228586
  • also called ago-alpha or variant 1
  • bind to and degrade MYC when overexpressed
  • mediates complex formation between USP28 and MYC
  • accounts for almost all of FBXW7 activity in the regulation of MYC and CCNE
  • 11 splicing initiation site 3751 70.2 627 cytosolic 2012 2228586
  • also called ago-beta or variant 2
  • differing by the N terminus alternative exon
  • not binding to MYC
  • high frequency of methylation of the promoter in thymoma, correlated with a high malignant potential (Gu 2008)
  • 11 - 3570 66 589 nucleolar 2012 2228586
  • also called variant 3, or gamma
  • bind to and degrade MYC when overexpressed
  • novel interaction partner, SYTL1, which binds the N-terminal domain of Fbw7-gamma
  • CDK2 also binds the N-terminal domain of Fbw7-gamma as well as SYTL1
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Hearing/Equilibriumear   highly
    Nervousbrain   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    Nervouscentral    Homo sapiensAdult
    Nervousperipherous    Homo sapiensAdult
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, checkpoint, G1S
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a highly hydrophobic stretch of 23 AA
  • a N terminal followed by a 40AAs F-box and seven WD40 repeats( critical role for the region upstream of the F-box and for the substrate binding domain)
  • HOMOLOGY
    interspecies ortholog to Fbxw7, Mus musculus
    ortholog to Fbxw7, Rattus norvegicus
    ortholog to fbxw7, Danio rerio
    ortholog to FBXW7, Pan troglodytes
    Homologene
    FAMILY
  • F-box protein family, FBWS class
  • CATEGORY tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    basic FUNCTION
  • substrate recognition subunit of SCF ubiquitin protein ligase complex
  • involved in regulating the G1-S cell cycle checkpoint by targeting proteins for destruction by the SCF compex of proteins
  • may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors
  • subunit of an SCF-type ubiquitin ligase complex, inducing the degradation of positive regulators of the cell cycle
  • functions as a fail-safe mechanism against both premature hematopoietic stem cells loss and leukemogenesis
  • acting as a negative regulator of several oncoproteins
  • acts as an E3 ubiquitin ligase that targets MYB for WNT/HIPK2/NLK-induced degradation
  • involved in FRAP1 targeted for ubiquitination and consequent degradation by binding
  • tumour suppressor at the crossroads of cell division, growth and differentiation
  • controls neural stem cell differentiation and apoptosis via NOTCH1 and JUN during embryonic development
  • negative regulator of adipogenesis by targeting CEBPA for degradation
  • could be an important regulator of energy and lipid metabolism
  • potentially blocks adipocyte differentiation by targeting CEBPA for degradation
  • potential novel regulator of TGFB signaling
  • could be an important regulator of TGFB signaling by targeting the transcriptional repressor TGIF1 for degradation
  • a key regulator of neural stem and progenitor cells viability and differentiation
  • controls neurogenesis by antagonizing Notch and c-Jun N-terminal kinase (JNK)/c-Jun signaling
  • key regulator of the maintenance and differentiation of neural stem cells in the brain
  • contributes to generation of the proper number and ratio of neurons and glial cells, a process that is essential for normal brain development
  • negative regulator of the Notch signaling pathway
  • essential during cerebellar development, and N-terminally phosphorylated JUN is an important substrate of FBXW7 during neurogenesis
  • FBXW7 and USP28 reciprocally regulated cell migration and angiogenesis in an HIF1A-dependent manner
  • role for FBXW7 in the processes of endothelial cell migration, angiogenesis, inflammation and barrier integrity, and provides novel insights into the regulation of KLF2 stability
  • limits the myelin-promoting activity of MTOR, thereby serving as an important brake on developmental myelination
  • FBXW7 helps tune the amount of myelin produced during development
  • CELLULAR PROCESS protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    text implicated in the ubiquitin-mediated turnover of cyclin E and the Notch/Lin-12 family of transcriptional activators
    PATHWAY
    metabolism
    signaling
    a component
  • one of the four subunits of the E3 ubiquitin protein ligase complex:(SCF) with SKP1, CUL1, RBX1, F-box protein bringing ubiquitin conjugating enzymes to substrates recruited by F-box
  • part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • presenilin 1, PS1
  • parkin
  • c-Myc
  • Skp1 and cyclin E
  • USP28
  • c-Myb
  • mammalian target of rapamycin, mTOR
  • inhibits breast cell proliferation at least partially through targeting KLF5 for proteolysis
  • TGIF1 )
  • interacting with IKBKG and MYC (interaction caused reduced ubiquitination of MYC by inhibiting ubiquitinating activity of FBXW7 without blocking the interaction between MYC and FBXW7)
  • substrate-binding component of an SCF ubiquitin ligase that degrades critical oncoproteins
  • EBNA1-binding protein 2 (EBNA1BP2) is the critical nucleolar factor that directly mediates FBXW7 nucleolar targeting
  • regulator of NFE2L1 expression, suggesting a novel function of FBXW7 in cellular stress response (FBXW7 regulates NFE2L1 via a CPD motif)
  • BMI1 has a critical role in stabilizing CCNE1 by repressing the expression of FBXW7, a substrate-recognition subunit of the SCF E3 ubiquitin ligase that targets CCNE1 for degradation
  • RICTOR is an important component of FBXW7 E3 ligase complex participating in the regulation of MYC and CCNE protein ubiquitination and degradation
  • GLMN modulates the E3 activity of CRL1(FBXW7)
  • posttranslational regulatory network in which the PTEN and FBXW7 pathways appear to converge on the regulation of Aurora-A level
  • NFKB2 is an interactor of the F-box protein FBXW7 (FBXW7-dependent degradation of NFKB2 functions as a prosurvival mechanism through control of NFKB activity)
  • MED13/MED13L physically link the CDK8 module to Mediator, and FBXW7 loss increases CDK8 module-Mediator association
  • zinc finger transcription factor Krüppel-like factor 2 (KLF2) is a physiological target of FBXW7 in endothelial cells
  • FBXW7 together with GSK3B negatively regulates CSF3R expression and its downstream signaling
  • CREB3L1 and CREB3L2 are substrates of FBXW7 controling osteogenesis and chondrogenesis by targeting CREB3L1 and CREB3L2, respectively, for degradation
  • MTOR is a functionally relevant target of FBXW7 in oligodendrocytes
  • NR1D1 is a core inhibitory component of clock transcription, targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7
  • cell & other
    REGULATION
    repressed by overexpression of FAM83D, that downregulates FBXW7 expression levels, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as MTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability
    tumoral     --low  
    in thymoma
    tumoral somatic mutation      
    in leukemic cells from more than 30p100 of patients with pediatric T-ALL and derived cell lines, and patients carrying FBXW7 and/or NOTCH1 mutations have a favorable overall survival
    tumoral        
    mutated or deleted in Wilms'tumor
    constitutional       loss of function
    promotes adipocyte differentiation of human adult stem cells
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    tumorthymus 
    target for therapeutic approaches in thymoma
    neurologyneurodegenerative 
    could be a target of myelin-promoting therapies
    ANIMAL & CELL MODELS
  • mice lacking the Fbw7 F-box protein die around 10.5 days post coitus because of a combination of deficiencies in hematopoietic and vascular development and heart chamber maturation
  • Fbxw7+/- mice have greater susceptibility to radiation-induced tumorigenesis
  • inactivation of Fbxw7 in hematopoietic cells causes premature depletion of hematopoietic stem cell (MID: 18367647)
  • absence of Fbw7 in the mouse brain caused severely impaired stem cell differentiation and increased progenitor cell death
  • neural stemness is potentially excessively maintained in Fbxw7-deficient mice