FBXO31 (F-box protein 31)

2008-06-01   Anthony J Bais 

Immunogene Therapy Surgical Research Division, Boston University School of Medicine, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908, USA

Identity

HGNC
LOCATION
16q24.2
LOCUSID
ALIAS
FBX14,FBXO14,Fbx31,MRT45,pp2386
FUSION GENES

DNA/RNA

Description

FBXO31 encodes one mRNA transcript, published analyses have not reordered alternative five prime transcript or start sequences.
  • FBXO31 is 3,635-bp in length, composed of 9 exons (1 to 9) spanning approximately 55-kb of genomic DNA, and has an ORF of 1,620-bp encoding a protein of 539 amino acids with a predicted mass of 61-kDa.
  • Alternative five prime transcripts may exist. Homologous mouse cDNA sequences extending further five prime have been used for RT-PCR to identify putative translation start sites and established that alternatively spliced five prime exons result in short and long isoforms. The short isoform is 3,635-bp in length (i.e. approximately with poly A), and is the predicted primary transcript. The long isoform is 3,725-bp in length, contains an additional five prime exon of 87-bp and has an ORF of 1,707-bp encoding a protein of 568 amino acids. An additional smaller isoform of 3,099-bp with an ORF of 1,104-bp and 367 amino acids was predicted in GenBank.
  • FBXO31 contains a moderate density C + G rich region (66% G + G with 9% CpG) spanning approximately 2.48-kb located within and five prime to the 350-bp exon 1.
  • The FBXO31 transcript has and an uncharacteristically short 23-bp five prime untranslated region.
  • Pseudogene

    None identified.

    Proteins

    Description

    FBXO31 contains no significant homology to other known proteins apart from a characteristic 40 amino acid F-box domain at the COOH-terminal end.
  • FBXO31 forms part of the FBXO class of F-box proteins. Comparison of FBXO31 with the F-box domain of functionally demonstrated F-box proteins (i.e. Fbx1, Fbx2, Fbw1a, Fbw1b and Fbl1 ) indicates that FBXO31 matches the F-box consensus more closely than recognized F-box proteins from each of the three classes. Most F-box proteins notated as FBXO do not have recognizable substrate binding domains. In one instance Fbx7 has been shown to contain a proline-rich region that functions with SCF complexes in regulating Cdk1 - cyclin B - phosphorylated hepatoma up-regulated protein ( HURP ) proteolysis. This proline-rich region has been found in other FBXO proteins. The COOH-terminal end of FBXO31 contains a 175-aa glycine and arginine rich region with possible similar function.
  • FBXO31 contains six minimal D-box (RxxL) motifs. Proteins with RxxL motifs are often degraded via the APC/C( Cdh1 ) ubiquitin ligase.
  • Expression

    FBXO31 is widely expressed as a 3.6-kb transcript at similar levels in breast, testis, ovary, liver, uterus, prostate, colon, stomach, bladder, spinal cord, pancreas, trachea, kidney and thyroid. High expression is found in brain and low expression in bone marrow. FBXO31 is represented by the unigene cluster Hs.567582. cDNA clones from Hs.567582 express in the adrenal gland, blood, colon, germ cells, heart, kidney, liver, lung, muscle, placenta, synovial membrane, tonsil, cervix, lymph tissue, skin, mammary gland, testis, ovary, uterus, prostate, stomach, bladder, spinal cord, pancreas, thyroid and brain.

    Localisation

    Co-immunoprecipitation experiments indicate that the carboxy terminal domain of FBXO31 associates with the Skp1, Roc-1 and Cullin-1 proteins. Immuno-localization studies demonstrate that ectopic expression of FBXO31 causes a change of Skp1 localization from the nucleus to the cytoplasm. The Skp1 protein returns to a nuclear localization when co-expressed with a FBXO31 protein with a deleted F-box domain.

    Function

    FBXO31 is associated with the Skp1, Roc-1 and Cullin-1 proteins through its substrate F-box recognition domain and forms part of an SCF ubiquitination complex.
    The ubiquitin-dependant proteasome degradation pathway regulates protein abundance and the function of oncogenes, tumor suppressors, transcription factors and other signaling molecules. Ubiquitination begins with the addition of ubiquitin moieties to target proteins and follows a multi-step process, the end point being proteolysis of polyubiquitinated substrates by a 26S multi-protein complex. Ubiquitination of substrates targeted for degradation requires 3 classes of enzymes; the ubiquitin-activating enzymes (E1), the ubiquitin conjugating enzymes (E2) and the ubiquitin ligases (E3). E3 proteins participate in cell cycle progression. SCF complexes (a class of E3 ligases) regulate the G1-S phase transition. A wide variety of SCF targets include G1 phase cyclins, cyclin-dependant kinase inhibitors, DNA replication factors and transcription factors that promote cell cycle progression.
    F-box containing proteins act as substrate recognition components of the SCF ubiquitin-ligase complexes in the ubiquitin-dependant proteasome degradation pathway. These complexes contain four components; Skp1, Cullin, Rbx-Rocl-Hrtl and an F-box protein. The F-box motif tethers the F-box protein to other components of the SCF complex by binding the core SCF component Skp1. This motif is generally found in the amino half of the proteins and is often coupled with other protein domains in the variable carboxy terminus of the protein. The most common carboxy terminal domains include leucine-rich repeats (LRRs) and WD-40 domains. Regions rich in glycine and arginine have also been implicated as protein binding domains, although such domains contain a more definitive repeat region than present in FBXO31.
    F-box SCF ubiquitin ligase complexes are involved in proteolysis pathways critical to diverse cellular functions including muscle atrophy, DNA metabolism, ER-associated degradation, desmin-related myopathy, signal transduction, control of G1-S progression and orderly execution of cell cycle. Skp1, Cul1 and Rbx1 are invariant proteins of the SCF complex while the F-box proteins that bind to Skp1 are the components that impart functional specificity. For instance Skp2 specifically binds phosphorylated p27 resulting in its degradation and control of S phase entry in the cell cycle.

    Homology

    F-box domain containing no other significant homology.

    Mutations

    Note

    None recorded.

    Implicated in

    Entity name
    Neurodegenerative disorders and cancer
    Note
    Aberrant ubiquitin-dependant proteasome degradation in neurodegenerative disorders and cancer.
    Precedence for disruption in neurodegenerative disorders. The Parkin gene functions as a E3 ubiquitin ligase often mutated in inherited forms of Parkinsons disease. In Alzheimers disease defective ubiquitination of cerebral proteins has been identified. The Von Hippel-Lindau ( VHL ) tumor suppressor protein is part of a complex that functions as a ubiquitin-protein ligase E3. VHL associates the ligase complex to target proteins such as HIF1aand VDU1 (VHL interacting deubiquitinating enzyme 1). HIF-a has been shown to regulate genes involved in tumor angiogenesis; VDU1 has deubiquitinating activity.
    Aberrant ubiquitin-dependant proteasome degradation of SCF-FBXO31 complexes has been proposed as a mechanism for tumor progression. FBXO31 would function as a tumor suppressor by mediating generation of SCF-FBXO31 complexes that compete and balance levels of other SCF complexes normally targeted to degradation proteins required to maintain cell proliferation. An example is SCF complexes resulting in SCF-Skp2 E3 ligases that mediate ubiquitination and subsequent degradation of the CDK-inhibitor p27. Ectopic expression of FBXO31 would lower SCF-Skp2 complexes resulting in increased p27 and inhibition of transition from G1-S phase. This model corroborates with studies showing that high levels of Skp2 were associated with reduced levels of p27 in several cancers.
    Fusion protein
    None recorded
    Entity name
    Breast cancer, Prostate cancer, and several other cancers
    Note
    Loss of heterozygosity (LOH) of 16q22-qter in breast cancer, prostate cancer, and several other cancers.
    This region is frequently deleted in several human cancers causing loss of heterozygosity. The 16q24.3 region including FBXO31 spans approximately 3-Mb from the marker D16S498 to the telomere and contains at least two smallest regions of overlap (SROs). These SROs are most frequently deleted in early and late stage breast cancer and in prostate cancer. Loss of normal function of FBXO31 may be a key event in the early stage of breast cancer. LOH on the whole 16q22-qter region is frequently detected in breast and prostate cancer. Micro-cell mediated transfer experiments with 16q22-qter fragments (the 360-kb YAC clone 792E1 at D16S476 and D16S498 and the 85-kb BAC clone 346J21 at D16S3048 and D16S3063) have been shown to induce senescence in human and rat breast tumor cell lines. FBXO31 encompasses the 792E1 clone and a partial region of 346J21, has been shown to induce senescence in the breast cancer cell line MCF-7 and is regarded as the cellular senescence gene. FBXO31 is a potential tumor suppressor shown to be down-regulated in breast cancer cell lines relative to normal breast expression and cause G1 phase cell cycle arrest of the MDA-MB-468 cell line.
    Quantitative gene expression analysis of 78 genes in the 16q24.3 region demonstrated that FBXO31 was one of two genes including CYBA with a moderately aberrant expression profile. Expression of FBXO31 was reduced 100 to 200-fold in MDA-MB-134 and SK-BR-3 and moderately reduced in the other cell lines. 68 other genes displayed normal expression, one displayed significantly aberrant expression ( CBFA2T3 ), six displayed mildly aberrant expression (DPEP1, CDH15, Hs.17074, Hs.189419, SLC7A5 and AA994450), and one gene displayed excessively reduced expression (CA5A). From microarray analysis FBXO31 was one of the 70-gene classifiers down-regulated in association with tumors of a favorable prognosis. The prognostic association between down-regulated FBXO31 and breast tumors corroborates with other studies demonstrating that LOH of chromosome 16q is associated with tumors of favorable prognosis.
    Disease
    16q22-qter LOH is detected in bilateral breast cancer and ductal lavage, in rare inflammatory breast cancer, and in several other cancers, including central nervous system neuroectodermal ependymoma and primary ependymomas, colorectal liver metastases, gastric tumor cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung tumor, nasopharyngeal tumor, ovarian tumor, rhabdomyosarcoma, and Wilms tumor. 16q22-qter LOH in ovarian, hepatocellular and particularly breast and prostate cancers, exhibit similar SROs, suggesting common molecular pathways are affected.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    103475521999Multiple polysomies in breast carcinomas: preferential gain of chromosomes 1, 5, 6, 7, 12, 16, 17, 18, and 19.Adeyinka A et al
    150829192004p27 deregulation in breast cancer: prognostic significance and implications for therapy.Alkarain A et al
    87061311996SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box.Bai C et al
    150145022004Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase.Bashir T et al
    94768961998The proteasome: paradigm of a self-compartmentalizing protease.Baumeister W et al
    125075552003Deregulated degradation of the cdk inhibitor p27 and malignant transformation.Bloom J et al
    105599161999SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.Carrano AC et al
    19789381990Allelic loss of chromosomes 16q and 10q in human prostate cancer.Carter BS et al
    105310351999Identification of a family of human F-box proteins.Cenciarelli C et al
    94610101998Frequent allelic loss on chromosomes 4q and 16q associated with human hepatocellular carcinoma in Taiwan.Chou YH et al
    108238312000Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.Cockman ME et al
    125082472003Genetic profiling of colorectal cancer liver metastases by combined comparative genomic hybridization and G-banding analysis.Diep CB et al
    108512372000Specific sequences of the Sm and Sm-like (Lsm) proteins mediate their interaction with the spinal muscular atrophy disease gene product (SMN).Friesen WJ et al
    93091161997Allelic imbalance mapping of chromosome 16 shows two regions of common deletion in prostate adenocarcinoma.Godfrey TE et al
    117174102001Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy.Gomes MD et al
    107114432000Allelic imbalance on 16q in small, unifocal hepatocellular carcinoma: correlation with HBV and HCV infections and cellular proliferation rate.Gramantieri L et al
    94095441997Pathways of ubiquitin conjugation.Haas AL et al
    153897802005Loss of heterozygosity in chromosomal region 16q24.3 associated with progression of prostate cancer.Härkönen P et al
    97594941998The ubiquitin system.Hershko A et al
    89824601996Ubiquitin-dependent protein degradation.Hochstrasser M et al
    151459412004Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region.Hsu JM et al
    105359401999Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex.Iwai K et al
    155580272005Functional identification of a BAC clone from 16q24 carrying a senescence gene SEN16 for breast cancer cells.Kaur GP et al
    119562082002The novel human DNA helicase hFBH1 is an F-box protein.Kim J et al
    111782632000The F-box protein family.Kipreos ET et al
    90672711997Loss of heterozygosity at chromosome 16q in prostate adenocarcinoma: identification of three independent regions.Latil A et al
    111040332000Loss of heterozygosity at chromosomes 3, 6, 8, 11, 16, and 17 in ovarian cancer: correlation to clinicopathological variables.Launonen V et al
    124480042002Evidence of chromosome regions and gene involvement in inflammatory breast cancer.Lerebours F et al
    110202232000Defective ubiquitination of cerebral proteins in Alzheimer's disease.López Salon M et al
    124975832003Clinical significance of chromosome 8p, 10q, and 16q deletions in prostate cancer.Matsuyama H et al
    13172581992A third Wilms' tumor locus on chromosome 16q.Maw MA et al
    104088661999Chromosome band 16q24 is frequently deleted in human gastric cancer.Mori Y et al
    108788072000Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.Ohh M et al
    99141801998SCF and APC: the Yin and Yang of cell cycle regulated proteolysis.Peters JM et al
    122132002002Sequencing, transcript identification, and quantitative gene expression profiling in the breast cancer loss of heterozygosity region 16q24.3 reveal three potential tumor-suppressor genes.Powell JA et al
    106449992000Identification of a YAC from 16q24 carrying a senescence gene for breast cancer cells.Reddy DE et al
    104908461999Identification of a gene at 16q24.3 that restores cellular senescence in immortal mammary tumor cells.Reddy DE et al
    146255362003Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover.Reed SI et al
    126209082003Fine mapping of Wilms' tumors with 16q loss of heterozygosity localizes the putative tumor suppressor gene to a region of 6.7 megabases.Safford SD et al
    13517531992Loss of heterozygosity on chromosome 16 in hepatocellular carcinoma.Sakai K et al
    95916281998Identification of a 910-kb region of common allelic loss in chromosome bands 16q24.1-q24.2 in human lung cancer.Sato M et al
    16820351991Accumulation of genetic alterations and progression of primary breast cancer.Sato T et al
    111910642000HIF-1: using two hands to flip the angiogenic switch.Semenza GL et al
    108888782000Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase.Shimura H et al
    122088642002Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer.Signoretti S et al
    94726421998The ubiquitin-proteasome pathway in cancer.Spataro V et al
    89462041996Three distinct commonly deleted regions of chromosome arm 16q in human primary and metastatic prostate cancers.Suzuki H et al
    16707631991Loss of heterozygosity on 6q, 16q, and 17p in human central nervous system primitive neuroectodermal tumors.Thomas GA et al
    21685601990Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma.Tsuda H et al
    93150991997Allelotype of pediatric rhabdomyosarcoma.Visser M et al
    100246911999Cervical metastases of head and neck squamous cell carcinoma correlate with loss of heterozygosity on chromosome 16q.Wang X et al
    147296092004Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers.Wang ZC et al
    105310371999A family of mammalian F-box proteins.Winston JT et al
    115265142001Identification of homozygous deletions at chromosome 16q23 in aflatoxin B1 exposed hepatocellular carcinoma.Yakicier MC et al
    117804682001Novel chromosomal alterations detected in primary nasopharyngeal carcinoma by comparative genomic hybridization.Yan J et al
    157564512005Loss of heterozygosity in ductal lavage for breast tumor and the contralateral breast.Yonekura Y et al
    121405602002E3 ubiquitin ligase that recognizes sugar chains.Yoshida Y et al
    19705541990Frequent loss of heterozygosity on chromosomes 16 and 4 in human hepatocellular carcinoma.Zhang WD et al
    111040272000Comparative genomic hybridization detects losses of chromosomes 22 and 16 as the most common recurrent genetic alterations in primary ependymomas.Zheng PP et al
    121981522002Timing of APC/C substrate degradation is determined by fzy/fzr specificity of destruction boxes.Zur A et al
    124685322003The small heat-shock protein alpha B-crystallin promotes FBX4-dependent ubiquitination.den Engelsman J et al
    118238602002Gene expression profiling predicts clinical outcome of breast cancer.van 't Veer LJ et al

    Other Information

    Locus ID:

    NCBI: 79791
    MIM: 609102
    HGNC: 16510
    Ensembl: ENSG00000103264

    Variants:

    dbSNP: 79791
    ClinVar: 79791
    TCGA: ENSG00000103264
    COSMIC: FBXO31

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000103264ENST00000311635Q5XUX0
    ENSG00000103264ENST00000565593H3BQG7
    ENSG00000103264ENST00000618298A0A0C4DGU8
    ENSG00000103264ENST00000636077A0A1B0GV77

    Expression (GTEx)

    0
    50
    100
    150

    Pathways

    PathwaySourceExternal ID
    Immune SystemREACTOMER-HSA-168256
    Adaptive Immune SystemREACTOMER-HSA-1280218
    Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
    Antigen processing: Ubiquitination & Proteasome degradationREACTOMER-HSA-983168

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    226329732012The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis.138
    194121622009F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.96
    163571372005FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex.27
    251153922014F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a.20
    248285032014SCF-FBXO31 E3 ligase targets DNA replication factor Cdt1 for proteolysis in the G2 phase of cell cycle to prevent re-replication.19
    261241082015F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress.19
    234690152013The centrosomal E3 ubiquitin ligase FBXO31-SCF regulates neuronal morphogenesis and migration.18
    249360622014F-box only protein 31 (FBXO31) negatively regulates p38 mitogen-activated protein kinase (MAPK) signaling by mediating lysine 48-linked ubiquitination and degradation of mitogen-activated protein kinase kinase 6 (MKK6).14
    215378372011FBXO31 determines poor prognosis in esophageal squamous cell carcinoma.12
    291179432018FBXO31 Suppresses Gastric Cancer EMT by Targeting Snail1 for Proteasomal Degradation.8

    Citation

    Anthony J Bais

    FBXO31 (F-box protein 31)

    Atlas Genet Cytogenet Oncol Haematol. 2008-06-01

    Online version: http://atlasgeneticsoncology.org/gene/44280/fbxo31