FBXO11 (F-box protein 11)

2014-09-01   Shanshan Duan , Michele Pagano 

Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA

Identity

HGNC
LOCATION
2p16.3
LOCUSID
ALIAS
FBX11,IDDFBA,PRMT9,UBR6,UG063H01,VIT1
FUSION GENES

Abstract

FBXO11 is a member of the F-box protein family, which is characterized by an approximately 40 amino acid motif, named the F-box domain. It is the substrate binding subunit of the SKP1-CUL1-F-box (SCF) ubiquitin ligase complex. FBXO11 is conserved from nematodes to mammals, and both human FBXO11 and its worm ortholog (DRE-1) form functional SCF ubiquitin ligase complexes. By binding to and mediating the degradation of its substrate proteins, FBXO11 plays important roles in regulating cell cycle regulation, tumorigenesis, and tumor cell metastasis. The gene encoding FBXO11 was found to be deleted or mutated in various types of human tumors.

DNA/RNA

Atlas Image
Figure 1.

Description

The gene is encoded by 23 exons that are located on chrosome 2p16.3 (NM_025133.4). The first ATG occurs in exon 2. There is an alternatively spliced transcript variant encoding an isoform in which the first ATG occurs in exon 1 (NM_001190274).

Transcription

3.8 kb mRNA; 2532 bp open reading frame (for NM_025133.4). 4 kb mRNA; 2784 bp open reading frame (for NM_001190274).

Proteins

Description

The fbxo11 gene encodes the FBXO11 protein which has 843 amino acids (NP_079409.3), with an estimated molecular weight of 94 kDa. The protein contains from N-term to C-term, an F-box domain, three CASH domains (domain present in carbohydrate binding proteins and sugar hydrolyses), and a Zinc finger domain. Other splice variants were reported (Cook et al., 2006).

Expression

Widely expressed.

Localisation

Mainly nuclear.
Atlas Image
Figure 2.

Function

Substrate recognition component of the SCFFBXO11 ubiquitin ligase complex consisting of CUL1, RBX1, SKP1 and FBXO11. Known interactors include p53, BCL6, CDT2, Blimp and Snail (Figure 2).
FBXO11 functions in lymphomagenesis
The SCFFBXO11 complex mediates ubiquitylation and degradation of BCL6, a transcription repressor that is required for normal germinal center development. Constitutive expression of BCL6 occurs in at least 70% patients with diffuse large B-cell lymphoma (DLBCL). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6 (Duan et al., 2012). Moreover, FBXO11 is deleted or mutated in 12-15% of primary DLBCL.
Fbxo11 in cell cycle regulation
FBXO11 interacts with CDT2 (a DCAF protein that controls cell-cycle progression) and recruits CDT2 to the SCFFBXO11 complex to promote its proteasomal degradation (Abbas et al., 2013; Rossi et al., 2013). CDK-mediated phosphorylation of Thr464 present in the CDT2 degron inhibits recognition by FBXO11 (Rossi et al., 2013). Inhibition of SCFFBXO11-mediated CDT2 degradation result in a delay in cell-cycle exit in response to serum deprivation or TGFβ treatment. The functional interaction between FBXO11 and CDT2 is evolutionary conserved from worms to humans and plays an important role in regulating the timing of cell-cycle exit.
FBXO11 in TGFβ signaling pathway
FBXO11 was implicated in the TGFβ signaling pathway. Mice with inactivated FBXO11 exhibited significant phospho-Smad2 (P-Smad2) nuclear staining in the epithelial cells of palatal shelves, eyelids, and airways of the lung, potentially leading to the developmental defects of these tissues (Tateossian et al., 2009).
SCFFBXO11-mediated degradation of CDT2 was shown to contribute to the stabilization of the CRL4CDT2 substrate p21 and Set8 in response to serum withdraw and TGFβ stimulation (Abbas et al., 2013; Rossi et al., 2013). Depletion of FBXO11 was shown also to inhibit lung adenocarcinoma eptithelial cells migration (Abbas et al., 2013).
FBXO11 in the regulation of cell metastasis
FBXO11 was shown to mediate the ubiquitylation and degradation of SNAIL (Zheng et al., 2014), a transcription factor that promotes epithelial-mesenchymal transition (EMT). The recognition of SNAIL by FBXO11 appears to be dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PDK1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models.
DRE-1/FBXO11 in C. elegans development
The C. elegans ortholog of FBXO11 is DRE-1, whose mutant phenotypes include precocious terminal differentiation of epidermal stem cells and altered temporal patterning of gonadal outgrowth (Fielenbach et al., 2007). DRE-1 forms a functional SCF ubiquitin ligase, and was reported to target the conserved transcription factor BLMP-1 for proteasomal degradation (Horn et al., 2014). The DRE-1 - BLMP-1 axis was important for regulating developmental timing within the heterochronic circuit during late larval development. blmp-1 deletion was shown to suppress dre-1 mutant phenotypes and exhibit developmental timing defects opposite to dre-1.
Other functions
FBXO11 has been shown to act as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 transcriptional activity. SCFFBXO11 does not mediate the ubiquitylation of p53 (Abida et al., 2007).

Homology

Human FBXO11 is highly conserved in evolution that shares 100% amino acid identity with Pan troglodytes, 99.8% identity with Canis lupus familiaris, 99.5% identity with Mus musculus, and 61% identity with C. elegans.

Mutations

Somatic

FBXO11-inactivating mutations contribute to the pathogenesis of diffuse large B cell lymphoma (DLBCL) through stabilization of BCL6 (Duan et al., 2012). FBXO11 mutations were also identified in other human cancers, such as colon, lung, ovary, and head and neck tumors (Kan et al., 2010; Lohr et al., 2012; Stransky et al., 2011; Yoshida et al., 2011). In mice, a homozygous mutation of Fbxo11 results in cleft palate defects, facial clefting, and perinatal lethality. Moreover, haploinsufficient mutant alleles cause otitis media, a disorder that affects approximately 15% of children (Hardisty-Hughes et al., 2006).

Implicated in

Note
FBXO11-inactivating mutations are found in human diffuse large B cell lymphoma (DLBCL), suggesting that FBXO11 may function as a tumor suppressor whose loss of function contributes to the pathogenesis of DLBCL through stabilization of BCL6.
Disease
Diffuse Large B-cell lymphoma.
Entity name
Otitis Media
Note
Genetic studies show a correlation between particular SNP variants of FBXO11 and the development of chronic otitis media (Segade et al., 2006).
Disease
Otitis media, inflammation of the middle ear, is the most common cause of hearing impairment in children.
Entity name
Vitiligo
Note
By comparing RNA isolated from vitiligo melanocyte cultures versus control cultures, VIT1 was found to be downregulated in vitiligo melanocytes, suggesting that it might be associated with this pigmentary disorder (Le Poole et al., 2001).
Disease
Vitiligo.

Bibliography

Pubmed IDLast YearTitleAuthors
234784452013CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration.Abbas T et al
170987462007FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity.Abida WM et al
217203652011Integrated genomic analyses of ovarian carcinoma.
164874882006FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues.Cook JR et al
221136142012FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas.Duan S et al
170352492006A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse.Hardisty-Hughes RE et al
246133962014DRE-1/FBXO11-dependent degradation of BLMP-1/BLIMP-1 governs C. elegans developmental timing and maturation.Horn M et al
206684512010Diverse somatic mutation patterns and pathway alterations in human cancers.Kan Z et al
117750602001'VIT1', a novel gene associated with vitiligo.Le Poole IC et al
223435342012Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing.Lohr JG et al
234784412013Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase.Rossi M et al
168471802006Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study.Segade F et al
217988932011The mutational landscape of head and neck squamous cell carcinoma.Stransky N et al
195806412009Regulation of TGF-beta signalling by Fbxo11, the gene mutated in the Jeff otitis media mouse mutant.Tateossian H et al
219091142011Frequent pathway mutations of splicing machinery in myelodysplasia.Yoshida K et al
252033222014PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.Zheng H et al

Other Information

Locus ID:

NCBI: 80204
MIM: 607871
HGNC: 13590
Ensembl: ENSG00000138081

Variants:

dbSNP: 80204
ClinVar: 80204
TCGA: ENSG00000138081
COSMIC: FBXO11

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000138081ENST00000402508Q86XK2
ENSG00000138081ENST00000403359Q86XK2
ENSG00000138081ENST00000405808B5MCV6
ENSG00000138081ENST00000424163C9IYF0
ENSG00000138081ENST00000434234E7EP88
ENSG00000138081ENST00000493962H0YAV3

Expression (GTEx)

0
10
20
30
40
50
60

References

Pubmed IDYearTitleCitations
221136142012FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas.97
252033222014PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.74
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
170987462007FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity.57
164874882006FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues.45
234784452013CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration.38
255897832015The oncogenic microRNA-21 inhibits the tumor suppressive activity of FBXO11 to promote tumorigenesis.36
258670612016MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity.33
168471802006Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study.30
168471802006Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study.30

Citation

Shanshan Duan ; Michele Pagano

FBXO11 (F-box protein 11)

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/gene/52605/fbxo11