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    FBXO4 F-box protein 4 [ Homo sapiens (human) ]

    Gene ID: 26272, updated on 2-Nov-2024

    Summary

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    Official Symbol
    FBXO4provided by HGNC
    Official Full Name
    F-box protein 4provided by HGNC
    Primary source
    HGNC:HGNC:13583
    See related
    Ensembl:ENSG00000151876 MIM:609090; AllianceGenome:HGNC:13583
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    FBX4
    Summary
    This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]
    Expression
    Ubiquitous expression in thyroid (RPKM 3.2), lymph node (RPKM 2.5) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See FBXO4 in Genome Data Viewer
    Location:
    5p13.1
    Exon count:
    9
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 5 NC_000005.10 (41925281..42040404)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 5 NC_060929.1 (42181685..42298494)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 5 NC_000005.9 (41925383..41941845)

    Chromosome 5 - NC_000005.10Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid active region 22508 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr5:41904130-41904676 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 22510 Neighboring gene zinc finger protein 626 pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15986 Neighboring gene Sharpr-MPRA regulatory region 10845 Neighboring gene ribosomal protein S2 pseudogene 22 Neighboring gene RAB7A interacting MON1-CCZ1 complex subunit 1 Neighboring gene MPRA-validated peak5238 silencer Neighboring gene ribosomal protein SA pseudogene 38 Neighboring gene methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase pseudogene 6 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr5:42078724-42079249 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr5:42090075-42091274 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_85089 Neighboring gene long intergenic non-protein coding RNA 2996 Neighboring gene NANOG hESC enhancer GRCh37_chr5:42225166-42225693 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_85146 Neighboring gene NANOG hESC enhancer GRCh37_chr5:42288621-42289193 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_85179 Neighboring gene GHR upstream promoter region module A Neighboring gene zinc finger protein 35 pseudogene Neighboring gene SERPINE1 mRNA binding protein 1 pseudogene 6 Neighboring gene growth hormone receptor

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Alternative splicing variants of human Fbx4 disturb cyclin D1 proteolysis in human cancer. Chu X, et al. Biochem Biophys Res Commun, 2014 Apr 25. PMID 24704453
    2. Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer. Barbash O, et al. Cancer Cell, 2008 Jul 8. PMID 18598945, Free PMC Article
    3. FBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells. Liu J, et al. Biochem Biophys Res Commun, 2021 May 21. PMID 33784509
    4. Regulation of FBXO4-mediated ICAM-1 protein stability in metastatic breast cancer. Kang JH, et al. Oncotarget, 2017 Oct 10. PMID 29137327, Free PMC Article
    5. Heat shock factor 1 deficiency via its downstream target gene alphaB-crystallin (Hspb5) impairs p53 degradation. Jin X, et al. J Cell Biochem, 2009 Jun 1. PMID 19343786, Free PMC Article

    See all (59) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. FBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells.
      Title: FBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells.
    2. in head and neck squamous cell carcinoma, fragile X mental retardation syndrome related protein 1 (Fxr1) overexpression correlates with reduced F-box protein 4 (Fbxo4) levels.
      Title: Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma.
    3. FBXO4 is the E3 ubiquitin ligase to interact with and promote Mcl-1 ubiquitination and degradation.
      Title: FBXO4 inhibits lung cancer cell survival by targeting Mcl-1 for degradation.
    4. results define the impact of alternative splicing on Fbx4 function, and suggest that the attenuated cyclin D1 degradation by these novel Fbx4 isoforms provides a new insight for aberrant cyclin D1 expression in human cancers.
      Title: Alternative splicing variants of human Fbx4 disturb cyclin D1 proteolysis in human cancer.
    5. The FBXO4 I377M mutant exhibits impaired cyclin D1 recruitment and ubiquitylation.
      Title: The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma.
    6. 14-3-3varepsilon binds to Ser12-phosphorylated Fbx4 to mediate dimerization and function.
      Title: Phosphorylation-dependent regulation of SCF(Fbx4) dimerization and activity involves a novel component, 14-3-3ɛ.
    7. Biochemical studies indicate that both the N-terminal domain and a loop connecting the linker and C-terminal domain of Fbx4 are critical for the dimerization and activation of the protein.
      Title: Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase.
    8. results reveal an atypical small GTPase domain within Fbx4 as a substrate-binding motif for SCF(Fbx4) and uncover a mechanism for selective ubiquitination and degradation of TRF1 in telomere homeostasis control
      Title: Structural basis of selective ubiquitination of TRF1 by SCFFbx4.
    9. Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer.
      Title: Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer.
    10. Fbx4 is a central regulator of Pin2/TRF1 protein abundance and alterations in the stability of Pin2/TRF1 can have a dramatic impact on telomere length
      Title: The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance.
    Submit: New GeneRIF Correction See all GeneRIFs (11)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Variation

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    See Variation Viewer (GRCh37.p13)

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ10141, DKFZp547N213

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein homodimerization activity IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables ubiquitin protein ligase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables ubiquitin-like ligase-substrate adaptor activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables ubiquitin-protein transferase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in cellular homeostasis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cellular response to ionizing radiation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cellular senescence IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in common myeloid progenitor cell proliferation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in negative regulation of fibroblast proliferation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in negative regulation of protein localization to nucleus IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of protein polyubiquitination IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of protein ubiquitination IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of telomere maintenance via telomerase IC
    Inferred by Curator
    more info
    		 PubMed 
    involved_in positive regulation of telomere maintenance via telomerase IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in post-transcriptional regulation of gene expression IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in protein destabilization IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in protein polyubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in protein polyubiquitination IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein ubiquitination IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein ubiquitination TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in regulation of DNA damage checkpoint IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in regulation of protein stability IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of protein stability IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in telomere maintenance IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in ubiquitin-dependent protein catabolic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    part_of SCF ubiquitin ligase complex IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    part_of SCF ubiquitin ligase complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  
    part_of ubiquitin ligase complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    F-box only protein 4
    Names
    F-box protein Fbx4

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    mRNA and Protein(s)

    1. NM_001297437.2 → NP_001284366.1  F-box only protein 4 isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks an internal exon in the 3' coding region, which results in a translational frameshift, compared to variant 1. The resulting isoform (3) is shorter and has a distinct C-terminus, compared to isoform 1.
      Source sequence(s)
      AC034222
      Consensus CDS
      CCDS75238.1
      UniProtKB/TrEMBL
      D6RAJ6
      Related
      ENSP00000421749.1, ENST00000509134.1
      Conserved Domains (2) summary
      cd11656
      Location:162 → 299
      FBX4_GTPase_like; C-terminal GTPase-like domain of F-Box Only Protein 4
      pfam12937
      Location:59 → 105
      F-box-like; F-box-like

    2. NM_012176.3 → NP_036308.1  F-box only protein 4 isoform 1

      See identical proteins and their annotated locations for NP_036308.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1).
      Source sequence(s)
      AC034222, AK024075, BC040011, BC048098
      Consensus CDS
      CCDS3938.1
      UniProtKB/Swiss-Prot
      Q68CU8, Q86VT8, Q9UK98, Q9UKT5
      UniProtKB/TrEMBL
      B3KNA0
      Related
      ENSP00000281623.3, ENST00000281623.8
      Conserved Domains (2) summary
      cd11656
      Location:162 → 384
      FBX4_GTPase_like; C-terminal GTPase-like domain of F-Box Only Protein 4
      pfam12937
      Location:59 → 100
      F-box-like; F-box-like

    3. NM_033484.3 → NP_277019.1  F-box only protein 4 isoform 2

      See identical proteins and their annotated locations for NP_277019.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks two exons and its transcription extends past a splice site that is used in variant 1, resulting in a novel 3' coding region and 3' UTR compared to variant 1. It encodes isoform 2 which is shorter and has a distinct C-terminus, compared to isoform 1.
      Source sequence(s)
      AC034222, AF176703, AU143782
      Consensus CDS
      CCDS3939.1
      UniProtKB/Swiss-Prot
      Q9UKT5
      Related
      ENSP00000296812.2, ENST00000296812.6
      Conserved Domains (2) summary
      cd11656
      Location:162 → 299
      FBX4_GTPase_like; C-terminal GTPase-like domain of F-Box Only Protein 4
      pfam12937
      Location:59 → 105
      F-box-like; F-box-like

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000005.10 Reference GRCh38.p14 Primary Assembly

      Range
      41925281..42040404
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011514026.4 → XP_011512328.1  F-box only protein 4 isoform X1

      Conserved Domains (2) summary
      cd11656
      Location:162 → 305
      FBX4_GTPase_like; C-terminal GTPase-like domain of F-Box Only Protein 4
      pfam12937
      Location:59 → 105
      F-box-like; F-box-like

    2. XM_011514027.3 → XP_011512329.1  F-box only protein 4 isoform X2

      Conserved Domains (1) summary
      cd11656
      Location:28 → 250
      FBX4_GTPase_like; C-terminal GTPase-like domain of F-Box Only Protein 4

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060929.1 Alternate T2T-CHM13v2.0

      Range
      42181685..42298494
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054352356.1 → XP_054208331.1  F-box only protein 4 isoform X1

    2. XM_054352357.1 → XP_054208332.1  F-box only protein 4 isoform X2

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9UKT5.2 GenPept UniProtKB/Swiss-Prot:Q9UKT5

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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