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RHOBTB1 (Rho-related BTB domain containing 1)

Written2008-12Kristina Schenková, Francisco Rivero
Centre for Biomedical Research, The Hull York Medical School, University of Hull, Cottingham Road, Hull HU6 7RX, UK
Updated2016-02Kristina Schenková, Shuo Cai, Francisco Rivero
Centre for Cardiovascular and Metabolic Research, The Hull York Medical School, University of Hull, Cottingham Road, Hull HU6 7RX, UK; kristina.schenkova@hyms.ac.uk, CaiS@cardiff.ac.uk, francisco.rivero@hyms.ac.uk

Abstract RhoBTB1 is one of the three members of the RhoBTB family. All RhoBTB proteins are characterized by a GTPase domain followed by a proline-rich region, a tandem of two BTB domains and a C-terminal putative RING finger domain. RHOBTB1 is a putative tumour suppressor gene. Expression of RHOBTB1 has been found decreased in diverse tumors including kidney, breast, stomach and colon cancers and head and neck squamous cell carcinomas. RhoBTB1 is a component of Cullin 3-dependent ubiquitin ligase complexes but its role in tumorigenesis is unknown.

Keywords tumor suppressor, ubiquitin ligase, cullin 3

(Note : for Links provided by Atlas : click)

Identity

Alias_namesRho-related BTB domain containing 1
Alias_symbol (synonym)KIAA0740
Other aliasMGC33059
MGC33841
HGNC (Hugo) RHOBTB1
LocusID (NCBI) 9886
Atlas_Id 42981
Location 10q21.2  [Link to chromosome band 10q21]
Location_base_pair Starts at 60869440 and ends at 60944275 bp from pter ( according to hg19-Feb_2009)  [Mapping RHOBTB1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ANK3 (10q21.2) / RHOBTB1 (10q21.2)RHOBTB1 (10q21.2) / ATP6V1C2 (2p25.1)RHOBTB1 (10q21.2) / TFAP2A (6p24.3)
RHOBTB1 (10q21.2) / ZRANB3 (2q21.3)

DNA/RNA

 
  Gene structure of RHOBTB1. Boxes represent exons. The coding region is represented in blue. For simplicity very large introns in the 5'UTR have been shortened (indicated by discontinuous lines)
Description The RHOBTB1 gene spans over 132 Kbp genomic DNA and consists of 14 exons, 9 coding exons and 5 more exons in the 5'UTR (Figure 1). The coding sequence of RHOBTB1 is 2091 nucleotides long (Ramos et al., 2002). The promoter region has a high GC content with numerous CpG islands. The RHOBTB1 locus has binding sites for retinoid X receptor and PPARA (peroxisome proliferator-activated receptor- α, as demonstrated by chromatin immunoprecipitation (Pelham et al., 2012).
Transcription Based on EST sequence analyses there are transcription variants that arise from the use of alternative promoters and alternative splicing, but none of the transcripts affects the coding region.

Protein

Note RhoBTB1 is one of the three members of the RhoBTB family in vertebrates. The RhoBTB family was identified during the study of the genes encoding Rho-related proteins in the lower eukaryote Dictyostelium discoideum (Rivero et al., 2002). All three RhoBTB proteins may be implicated in tumorigenesis.
 
  Architecture of RhoBTB proteins. The figure shows the three human (Hs) RhoBTB subfamily members as well as the Drosophila (Dm) and Dictyostelium (Dd) orthologues. The simplified phylogenetic tree on the left illustrates the relationship among the proteins (overall percentage similarity between branches). The different domains are indicated with colours.
Description RhoBTB1 is 696 amino acids long. All RhoBTB proteins share the same domain architecture: a GTPase domain is followed by a proline-rich region, a tandem of two BTB domains and a C-terminal region (Figure 2). The GTPase domain is Rho-related and contains a Rho insert that is longer than usual, two insertions and one deletion, as well as a few deviations from the GTPase consensus of most Rho GTPases. In analogy to RhoBTB2, the GTPase domain of RhoBTB1 is likely to bind GTP (Manjarrez et al., 2014).
The proline-rich region links the GTPase to the first BTB domain. This region could act as a SH3 domain-binding site.
The BTB domain (broad complex, tramtract and bric-a-brac) is an evolutionary conserved protein-protein interaction domain that participates in homomeric and heteromeric associations with other BTB domains. The BTB domain was also identified as a component of multimeric cullin3-dependent ubiquitin ligase complexes. The first BTB domain is bipartite, being interrupted by an insertion of unknown function. The BTB domains of RhoBTB allow the formation of homodimers and of heterodimers with other proteins of the RhoBTB family (Berthold et al., 2008).
The C-terminus is a region conserved in all members of the RhoBTB subfamily. It predictably folds as 4 consecutive alpha-helices and one beta-strand and may constitute a RING finger domain (Manjarrez et al., 2014). Many RING finger domains function as ubiquitin ligases. RhoBTB1 does not bear a CAAX motif that is typical for classical Rho GTPases and serves for localization of the protein to membranes.
Expression RHOBTB1 is ubiquitously expressed, with high levels detected in skeletal muscle, placenta, stomach, kidney, testis, ovary, uterus and adrenal gland. The gene is also expressed in foetal tissues (Ramos et al., 2002; Nagase et al., 1998).
Expression of RHOBTB1 has been found decreased in kidney, breast and stomach tumors in a cancer profiling array (Berthold et al., 2008), in 37% of 46 head and neck squamous cell carcinomas (Beder et al., 2006) and in colon cancer tissues (Xu et al., 2013).
RHOBTB1 is a target of the microRNA MIR31- (Alder et al., 2012; Xu et al., 2013).
Localisation The localisation of endogenous RhoBTB1 has not been investigated. In cells expressing RhoBTB1 ectopically the protein tends to form aggregates in the cytoplasm (Aspenström et al., 2004).
Function RHOBTB1 has been proposed as a candidate tumour suppressor gene (Beder et al., 2006). The mechanisms by which RhoBTB proteins in general exert this and other roles remain speculative. Much of what we know about RhoBTB2 may be made extensive to RhoBTB1 because of their similarity.
RhoBTB1 binds to cullin3 and by analogy to RhoBTB2 and RhoBTB3 may constitute ubiquitin ligase complexes. RhoBTB proteins appear to exist in an inactive state through an intramolecular interaction of the BTB domain region with the GTPase domain (Berthold et al., 2008). This model has been refined recently for RhoBTB2 to show that the HSP90AA1 (Hsp90) chaperone machinery unlocks RhoBTB, enabling GTP binding and interaction with Cullin 3 and the COPS8 (COP9) signalosome. COP9 deneddylates Cullin 3 and stabilizes the complex (Manjarrez et al. 2014). Considering the high degree of similarity between RhoBTB2 and RhoBTB1, this mechanism is very likely to apply to RhoBTB1 too.
RHOBTB1 has been identified as a target gene of the nuclear hormone receptor PPARG. RhoBTB1 mRNA and protein levels are decreased in the aorta of mice expressing a dominant negative PPARG. These mice also present a concomitant decrease in Cullin 3, and it has been proposed that RhoBTB1 regulates Cullin 3 levels or activity, which in turn regulates RHOA. turnover in smooth muscle. RhoBTB1 emerges as a component of a signaling mechanism that regulates vascular function and blood pressure (Pelham et al., 2012).
RhoBTB1, like RhoBTB2, is required for expression of the chemokine CXCL14 in keratinocytes independently of Cullin3-mediated protein degradation (McKinnon et al., 2008).
RhoBTB1 displays only a moderate influence on the morphology and actin organisation of porcine aortic endothelial cells upon ectopic expression. It does not interact with the GTPase-binding domain of WASP, PAK1 or RTKN (Rhotekin), which are well-known effectors of many typical Rho GTPases (Aspenstrom et al., 2004).
RhoBTB1, like RhoBTB2 and RhoBTB3, interacts with LLRC41 (leucine rich repeat containing 41, MUF1). MUF-1 is a nuclear protein and carries a BC-box that functions as a linker in multicomponent Cullin 5-dependent ubiquitin ligase complexes (Schenková et al., 2012). MUF1 may be a substrate for RhoBTB-Cullin 3 ubiquitin ligase complexes. The function of MUF1 is unknown, but it is suspected to be involved in the DNA damage response
Homology There are three RhoBTB proteins in vertebrates: RhoBTB1, RhoBTB2 and RhoBTB3 (Figure 2). RhoBTB1 is very similar to RhoBTB2, while RhoBTB3 displays very low similarity to these. Orthologues have been found in amoebae and in insects but they are absent in plants and fungi.

Mutations

Note No pathogenic mutations have been identified to date.

Implicated in

Note
  
Entity Head and neck squamous cell carcinoma
Note RHOBTB1 resides in a hotspot region with high frequency of allelic loss in HNSCCs. Loss of heterozygosity at the RHOBTB1 locus was identified in 12 of 52 tumour samples. RHOBTB1 showed decreased expression levels in 37% of 46 tumour samples and all informative low-expression samples displayed loss of heterozygosity. Three silent nucleotide changes were found in a mutation analysis (Beder et al., 2006).
Oncogenesis RhoBTB1, along with RhoBTB2, seems to be required for expression of the chemokine CXCL14 (McKinnon et al., 2008). CXCL14 controls leukocyte migration and angiogenesis and its expression is frequently lost in diverse epithelial tumours, including most HNSCCs.
  
  
Entity Colon cancer
Note RhoBTB1 levels were found decreased in colon cancer specimens using immunohistochemistry and Western blot. RHOBTB1 was identified as a target of miR-31 using bioinformatics tools, and the effect of miR-31 was verified experimentally. Downregulation of RHOBTB1 is responsible for the tumor promoting effects of miR-31. Silencing of RHOBTB1 in the colon cancer cell line HT29 increases cell proliferation and promotes cell clonal growth, mimicking the effects of increased miR-31 expression (Xu et al., 2013).
  
  
Entity Esophageal cancer
Note Overexpression of miR-31 in esophagus caused by zinc deficiency was found associated to down-regulation of RHOBTB1, which was identified as a target gene of miR-31. Zinc deficiency is a risk factor for the development of esophageal squamous cell carcinoma (Alder et al., 2012).
  
  
Entity Various cancers including breast, kidney and stomach
Note Expression of RHOBTB1 was found moderately but significantly decreased in kidney, breast and stomach tumour samples in a cancer profiling array. The decrease affected to 80% of kidney and to 58% of breast cancer samples. The expression changes correlated with those of CUL3 in the same samples (Berthold et al., 2008)
  

Bibliography

Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer.
Alder H, Taccioli C, Chen H, Jiang Y, Smalley K, Fadda P, Ozer HG, Huebner K, Farber JL, Croce CM, Fong LYY.
Carcinogenesis 2012; 33: 1736-1744.
PMID 22689922
 
Rho GTPases have diverse effects on the organization of the actin filament system.
Aspenströ P, Fransson A, Saras J.
Biochem J 2004? 377: 327-337.
PMID 14521508
 
Identification of a candidate tumor supressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer.
Beder LB, Gunduz M, Ouchida M, Gunduz E, Sakai A, Fukushima K, Nagatsuka H, Ito S, Honjo N, Nishizaki K, Shimizu K.
J Cancer Res Clin Oncol 2006? 132: 19-27.
PMID 16170569
 
Rho GTPases of the RhoBTB subfamily and tumorigenesis.
Berthold J, Schenková K, Rivero F.
Acta Pharmacol Sin 2008; 29: 285-295. (Review)
PMID 18298893
 
Hsp90-dependent assembly of the DBC2/RhoBTB2-Cullin3 E3-ligase complex.
Manjarrez JR, Sun L, Prince T, Matts RL.
PLoS One 2014; 9: e90054
PMID 24608665
 
The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells.
McKinnon CM, Lygoe KA, Skelton L, Mitter R, Mellor H.
Oncogene 2008; 27: 6856-6865.
PMID 18762809
 
Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.
Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O.
DNA Res 1999; 5: 277-286.
PMID 9872452
 
Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPAR? and RhoA/Rho-kinase.
Pelham CJ, Ketsawatsomkron P, Groh S, Grobe JL, de Lange WJ, Ibeawuchi S-RC, Keen HL, Weatherford ET, Faraci FM, Sigmund CD.
Cell Metab 2012; 16: 462-472.
PMID 23040068
 
Genomic organization and expression profile of the small GTPases of the RhoBTB family in human and mouse.
Ramos S, Khademi F, Somesh BP, Rivero F.
Gene 2002? 298: 147-157.
PMID 12426103
 
The Dictyostelium discoideum family of Rho-related proteins.
Rivero F, Dislich H, Glöckner G, Noegel AA.
Nucleic Acids Res 2001; 29: 1068-1079.
PMID 11222756
 
MUF1/Leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent Cullin 3 ubiquitin ligase complexes, is a predominantly nuclear dimeric protein.
Schenková K, Lutz J, Kopp M, Ramos S, Rivero F.
J Mol Biol 2012; 422: 659 - 673.
PMID 22709582
 
The tumor suppressor gene RhoBTB1 is a novel target of miR-31 in human colon cancer.
Xu RS, Wu XD, Zhang SQ, Li CF, Yang L, Li DD, Zhang BG, Zhang Y, Jin JP, Zhang B.
Int J Oncol 2013; 42: 676-682.
PMID 23258531
 

Citation

This paper should be referenced as such :
Schenková K, Cai S, Rivero F
RHOBTB1 (Rho-related BTB domain containing 1);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/RHOBTB1ID42981ch10q22.html
History of this paper:
Schenkova, K ; Rivero, F. RHOBTB1 (Rho-related BTB domain containing 1). Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):865-867.
http://documents.irevues.inist.fr/bitstream/handle/2042/44617/12-2008-RHOBTB1ID42981ch10q22.pdf


External links

Nomenclature
HGNC (Hugo)RHOBTB1   18738
Cards
AtlasRHOBTB1ID42981ch10q22
Entrez_Gene (NCBI)RHOBTB1  9886  Rho related BTB domain containing 1
Aliases
GeneCards (Weizmann)RHOBTB1
Ensembl hg19 (Hinxton)ENSG00000072422 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000072422 [Gene_View]  chr10:60869440-60944275 [Contig_View]  RHOBTB1 [Vega]
ICGC DataPortalENSG00000072422
TCGA cBioPortalRHOBTB1
AceView (NCBI)RHOBTB1
Genatlas (Paris)RHOBTB1
WikiGenes9886
SOURCE (Princeton)RHOBTB1
Genetics Home Reference (NIH)RHOBTB1
Genomic and cartography
GoldenPath hg38 (UCSC)RHOBTB1  -     chr10:60869440-60944275 -  10q21.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RHOBTB1  -     10q21.2   [Description]    (hg19-Feb_2009)
EnsemblRHOBTB1 - 10q21.2 [CytoView hg19]  RHOBTB1 - 10q21.2 [CytoView hg38]
Mapping of homologs : NCBIRHOBTB1 [Mapview hg19]  RHOBTB1 [Mapview hg38]
OMIM607351   
Gene and transcription
Genbank (Entrez)AB018283 AI935070 AK075129 AK307630 AK309440
RefSeq transcript (Entrez)NM_001242359 NM_001350902 NM_001350903 NM_001350904 NM_001350905 NM_001350906 NM_001350907 NM_001350908 NM_001350909 NM_001350910 NM_001350911 NM_014836
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RHOBTB1
Cluster EST : UnigeneHs.737374 [ NCBI ]
CGAP (NCI)Hs.737374
Alternative Splicing GalleryENSG00000072422
Gene ExpressionRHOBTB1 [ NCBI-GEO ]   RHOBTB1 [ EBI - ARRAY_EXPRESS ]   RHOBTB1 [ SEEK ]   RHOBTB1 [ MEM ]
Gene Expression Viewer (FireBrowse)RHOBTB1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9886
GTEX Portal (Tissue expression)RHOBTB1
Human Protein AtlasENSG00000072422-RHOBTB1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO94844   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO94844  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO94844
Splice isoforms : SwissVarO94844
PhosPhoSitePlusO94844
Domaine pattern : Prosite (Expaxy)BTB (PS50097)    RHO (PS51420)   
Domains : Interpro (EBI)BTB/POZ_dom    P-loop_NTPase    SKP1/BTB/POZ    Small_GTPase   
Domain families : Pfam (Sanger)BTB (PF00651)    Ras (PF00071)   
Domain families : Pfam (NCBI)pfam00651    pfam00071   
Domain families : Smart (EMBL)BTB (SM00225)  
Conserved Domain (NCBI)RHOBTB1
DMDM Disease mutations9886
Blocks (Seattle)RHOBTB1
SuperfamilyO94844
Human Protein Atlas [tissue]ENSG00000072422-RHOBTB1 [tissue]
Peptide AtlasO94844
HPRD06299
IPIIPI00001317   IPI01014528   
Protein Interaction databases
DIP (DOE-UCLA)O94844
IntAct (EBI)O94844
FunCoupENSG00000072422
BioGRIDRHOBTB1
STRING (EMBL)RHOBTB1
ZODIACRHOBTB1
Ontologies - Pathways
QuickGOO94844
Ontology : AmiGOGTPase activity  GTP binding  cytosol  plasma membrane  small GTPase mediated signal transduction  regulation of small GTPase mediated signal transduction  
Ontology : EGO-EBIGTPase activity  GTP binding  cytosol  plasma membrane  small GTPase mediated signal transduction  regulation of small GTPase mediated signal transduction  
Pathways : KEGGUbiquitin mediated proteolysis   
REACTOMEO94844 [protein]
REACTOME PathwaysR-HSA-194840 [pathway]   
NDEx NetworkRHOBTB1
Atlas of Cancer Signalling NetworkRHOBTB1
Wikipedia pathwaysRHOBTB1
Orthology - Evolution
OrthoDB9886
GeneTree (enSembl)ENSG00000072422
Phylogenetic Trees/Animal Genes : TreeFamRHOBTB1
HOVERGENO94844
HOGENOMO94844
Homologs : HomoloGeneRHOBTB1
Homology/Alignments : Family Browser (UCSC)RHOBTB1
Gene fusions - Rearrangements
Fusion : MitelmanANK3/RHOBTB1 [10q21.2/10q21.2]  [t(10;10)(q21;q21)]  
Fusion : MitelmanRHOBTB1/ATP6V1C2 [10q21.2/2p25.1]  [t(2;10)(p25;q21)]  
Fusion: TCGA_MDACCANK3 10q21.2 RHOBTB1 10q21.2 BRCA
Fusion: TCGA_MDACCRHOBTB1 10q21.2 ATP6V1C2 2p25.1 BRCA
Tumor Fusion PortalRHOBTB1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRHOBTB1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RHOBTB1
dbVarRHOBTB1
ClinVarRHOBTB1
1000_GenomesRHOBTB1 
Exome Variant ServerRHOBTB1
ExAC (Exome Aggregation Consortium)ENSG00000072422
GNOMAD BrowserENSG00000072422
Genetic variants : HAPMAP9886
Genomic Variants (DGV)RHOBTB1 [DGVbeta]
DECIPHERRHOBTB1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRHOBTB1 
Mutations
ICGC Data PortalRHOBTB1 
TCGA Data PortalRHOBTB1 
Broad Tumor PortalRHOBTB1
OASIS PortalRHOBTB1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRHOBTB1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRHOBTB1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch RHOBTB1
DgiDB (Drug Gene Interaction Database)RHOBTB1
DoCM (Curated mutations)RHOBTB1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RHOBTB1 (select a term)
intoGenRHOBTB1
NCG5 (London)RHOBTB1
Cancer3DRHOBTB1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607351   
Orphanet
DisGeNETRHOBTB1
MedgenRHOBTB1
Genetic Testing Registry RHOBTB1
NextProtO94844 [Medical]
TSGene9886
GENETestsRHOBTB1
Target ValidationRHOBTB1
Huge Navigator RHOBTB1 [HugePedia]
snp3D : Map Gene to Disease9886
BioCentury BCIQRHOBTB1
ClinGenRHOBTB1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9886
Chemical/Pharm GKB GenePA38664
Clinical trialRHOBTB1
Miscellaneous
canSAR (ICR)RHOBTB1 (select the gene name)
Probes
Litterature
PubMed22 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRHOBTB1
EVEXRHOBTB1
GoPubMedRHOBTB1
iHOPRHOBTB1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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