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BEX2 (brain expressed X-linked 2)

Written2012-01Biaoyang Lin, Jing Zhang, Greg Foltz
Swedish Medical Center, Seattle, WA, USA (BL, GF); Zhejiang-California International NanoSystems Institute, Zhejiang Univ Hangzhou, China (BL, JZ)

(Note : for Links provided by Atlas : click)


Alias (NCBI)BEX1
HGNC (Hugo) BEX2
HGNC Alias symbDJ79P11.1
LocusID (NCBI) 84707
Atlas_Id 44162
Location Xq22.1  [Link to chromosome band Xq22]
Location_base_pair Starts at 103309346 and ends at 103310990 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping BEX2.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)
DDX21 (10q22.1) / BEX2 (Xq22.1)


Note There was some confusion in the nomenclature of the human BEX genes. The BEX1 referred in the publications (Quentmeier et al., 2005; Yang et al., 2002) is actually BEX2. BEX2, represented by the Genbank accession number AF220189, was called BEX1 by Yang et al. and others (Quentmeier et al., 2005; Yang et al., 2002). Later on, Alvarez et al. found that AF220189 is more similar to mouse Bex2 than to mouse Bex1 (74% and 68% identical, respectively) and that its chromosomal localization matches that of mouse Bex2 (Alvarez et al., 2005). Therefore, AF220189 is considered the human homologue of mouse Bex2, and is human BEX2.
  A diagram using the UCSC genome browser showing the locations of the five BEX members in the order of BEX5-BEX1-BEX4-BEX2-NGFRAP1 (nerve growth factor receptor (TNFRSF16) associated protein 1, BEX3) on the X chromosome at Xq22.1-2, along with other genes in the region.
Description BEX2 encodes a gene belonging to the brain expressed X-linked gene family. It is a putative tumor suppressor as it is silenced in human glioma (Foltz et al., 2006). The BEX2 gene contains three exons and each of them encodes part of the coding region. This is in contrast with BEX1, for which the coding region was encompassed by one single exon.
Transcription The BEX2 transcript (originally named BEX1 in Yang et al.'s paper) is highly expressed in brain, pancreas, testis, and ovary, but is expressed at lower levels in heart, placenta, liver, kidney, spleen, thymus, prostate, small intestine, colon (no mucus), thyroid, spinal cord, and adrenal gland. It is not expressed in lung, skeletal muscle, peripheral blood leukocyte, stomach, lymph node, trachea, and bone marrow (Yang et al., 2002).


Note BEX2 interacts with LMO2 (LIM domain only 2 (rhombotin-like 1)) (Behrens et al., 2003; Han et al., 2005), a LIM-domain containing transcriptional factor. The interaction between BEX2 and LMO2 may bind to NSCL2 (NHLH2, nescient helix loop helix 2), a neuronal bHLH protein, to regulate NSCL2-dependent transcriptional activity (Han et al., 2005).
Description BEX2 has multiple protein isoforms. In one isoform (NP_116010.1), it contains 128 amino acid residues.
Expression Koo et al. assessed the expression pattern of Bex proteins in several different mouse tissues by western blot analysis (Koo et al., 2004). They used a polyclonal chicken antibody directed against a peptide common to the C-terminal region of mouse Bex1 and -2, which are 87% identical and 90% similar in amino acid sequences. They found that Bex1 and -2 proteins are expressed in mouse whole brain without olfactory bulb, olfactory bulb, olfactory epithelium and at a lower level in the heart, kidney, and liver but, not in the lung (Koo et al., 2004).
Localisation Nucleus and cytoplasm (Koo et al., 2004).
Function BEX2 is required for the normal cell cycle progression during G1 in breast cancer cells by regulating cyclin D1 and p21 (Naderi et al., 2010a). BEX2 also protects the breast cancer cells against mitochondrial apoptosis. This process was achieved through the positive regulation of anti-apoptotic member Bcl-2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA (Naderi et al., 2010a).
Homology Five BEX members have been identified in human. They are BEX1, BEX2, NGFRAP1 (nerve growth factor receptor (TNFRSF16) associated protein 1, BEX3), BEX4, and BEX5. They are all clustered on the X chromosome at Xq22.1-2 (Alvarez et al., 2005).


Note None identified.

Implicated in

Entity Glioma
Note We showed that BEX1 and BEX2 are candidate tumor suppressor genes in malignant glioma in a genome-wide analysis of epigenetic silencing in gliomas (Foltz et al., 2006). We found that BEX1 and BEX2 were reactivated by trichostatin A (TSA), a histone deacetylase inhibitor, or 5-aza-2'-deoxycytidine (5-AzaC), a DNA methyltransferase inhibitor in glioma cell line T98 and U87, and 10 patient-derived primary glioma cell lines (Foltz et al., 2006). We demonstrated that BEX1 and BEX2's expression were silenced in GBM specimens because of extensive promoter hypermethylation at their promoters. Re-expression of either BEX1 or BEX2 led to increased sensitivity to chemotherapy-induced apoptosis and potent tumor suppressor effects in vitro and in a xenograft mouse model (Foltz et al., 2006). We further showed that BEX1 and BEX2 in GBM cells were down regulated by SOX2, a key gene implicated in maintaining the stemness of embryonic and adult stem cells (Fang et al., 2011).
Le Mercier et al. showed that decreasing BEX2 expression in Hs683 oligodendroglioma cells increased the survival of Hs683 orthotopic xenograft-bearing mice via modulating genes involved in cancer cell migration, such as MAP2, plexin C1, SWAP70, and integrin beta and impairments of vasculogenic mimicry channel formation in vitro and angiogenesis in vivo (Le Mercier et al., 2009).
Disease Gliomas are the primary cancers derived from glial cells in the brain. It is the most frequent cerebral neoplasias. Astrocytomas are the most common type of gliomas. They are slow-growing, and can be found anywhere in the brain, but most often found in the cerebrum. They can be clinically divided into four grades, with glioblastoma (World Health Organization grade IV) being the most common and aggressive. Oligodendrogliomas are a type of glioma originating from the oligodendrocytes of the brain or from a glial precursor cell.
Entity Breast cancer
Note Naderi et al. showed that BEX2 protein was overexpressed in approximately 50% of malignant breast tumors compared to only 7% of benign breast samples (Naderi et al., 2012). Furthermore, they showed that BEX2 positive tumors identified a subset of breast cancers with the overexpression of ErbB2 and phosphorylated c-Jun proteins (Naderi et al., 2012). They went on to demonstrate that BEX2 downregulation induced mitochondrial apoptosis and sensitizes breast cancer cells to the pro-apoptotic effects of ceramide, doxorubicin and staurosporine (Naderi et al., 2010a). The role of BEX2 in apoptosis is mediated through the modulation of Bcl-2 protein family - it positively regulates anti-apoptotic member Bcl-2 and negatively regulates pro-apoptotic members BAD, BAK1 and PUMA (Naderi et al., 2010a). BEX2 is also required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of cyclin D1 and p21 (Naderi et al., 2010a). BEX2 overexpression also activates the Bcl-2/NF-kappaB pathway in primary breast tumors (Naderi et al., 2010a). c-Jun and p65/RelA bind to the BEX2 promoter and turn on the expression of BEX2 (Naderi et al., 2010b). Interestingly, BEX2 in turn regulates the phosphorylation/activity of c-Jun and p65/RelA, suggesting that BEX2 is involved in a novel feedback mechanism in breast cancer cells (Naderi et al., 2010b).
Disease Breast cancer forms in the tissues of one or both breasts. It primarily affects women, but can also occur in children and men. It can be a highly curable disease if detected and treated early.
Entity Acute myeloid leukemia
Note Acute myeloid leukemia (AML) with mixed lineage leukemia (MLL) was defined by the translocation of the mixed lineage leukemia (MLL) gene, which occurs most frequently in infant acute lymphoblastic leukemia and secondary AML. Quentmeier et al. identified BEX2 (was named BEX1 in the original publication) as over expressed and could be used as candidate gene for the diagnosis of acute myeloid leukemia (AML) with mixed lineage leukemia (MLL) translocations (Quentmeier et al., 2005). Fischer et al. (Fischer et al., 2007) and Röhrs et al. (Röhrs et al., 2009) showed that both the HDAC inhibitor trichostatin A (TSA) and the demethylating agent 5-Aza-20deoxycytidine (Aza) substantially increased the expression of BEX2 mRNA in MLL wild-type (MLLwt) cells, suggesting that BEX2 is an epigenetically regulated gene (Fischer et al., 2007; Röhrs et al., 2009). Röhrs et al. found that MLL fusion proteins seemed to be responsible for the hypomethylation and higher expression of the tumor suppressor gene BEX2 in acute myeloid leukemia (AML) with mixed lineage leukemia (MLL) translocations (Röhrs et al., 2009).
Disease Acute myeloid leukemia (AML), one of the most common types of leukemia among adults, is caused by abnormal growth of the cells that would otherwise normally turn into white blood cells inside the bone marrow. It generally occurs around age 60.


Characterization of the Bex gene family in humans, mice, and rats.
Alvarez E, Zhou W, Witta SE, Freed CR.
Gene. 2005 Aug 29;357(1):18-28.
PMID 15958283
Identification of members of the Bex gene family as olfactory marker protein (OMP) binding partners.
Behrens M, Margolis JW, Margolis FL.
J Neurochem. 2003 Sep;86(5):1289-96.
PMID 12911636
The SOX2 response program in glioblastoma multiforme: an integrated ChIP-seq, expression microarray, and microRNA analysis.
Fang X, Yoon JG, Li L, Yu W, Shao J, Hua D, Zheng S, Hood L, Goodlett DR, Foltz G, Lin B.
BMC Genomics. 2011 Jan 6;12:11.
PMID 21211035
Epigenetic regulation of brain expressed X-linked-2, a marker for acute myeloid leukemia with mixed lineage leukemia rearrangements.
Fischer C, Drexler HG, Reinhardt J, Zaborski M, Quentmeier H.
Leukemia. 2007 Feb;21(2):374-7.
PMID 17251904
Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma.
Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J, Frakes A, Lee H, Field L, Zander K, Sibenaller Z, Ryken TC, Vibhakar R, Hood L, Madan A.
Cancer Res. 2006 Jul 1;66(13):6665-74.
PMID 16818640
Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex.
Han C, Liu H, Liu J, Yin K, Xie Y, Shen X, Wang Y, Yuan J, Qiang B, Liu YJ, Peng X.
Nucleic Acids Res. 2005 Nov 24;33(20):6555-65. Print 2005.
PMID 16314316
The interaction of Bex and OMP reveals a dimer of OMP with a short half-life.
Koo JH, Gill S, Pannell LK, Menco BP, Margolis JW, Margolis FL.
J Neurochem. 2004 Jul;90(1):102-16.
PMID 15198671
Galectin 1 proangiogenic and promigratory effects in the Hs683 oligodendroglioma model are partly mediated through the control of BEX2 expression.
Le Mercier M, Fortin S, Mathieu V, Roland I, Spiegl-Kreinecker S, Haibe-Kains B, Bontempi G, Decaestecker C, Berger W, Lefranc F, Kiss R.
Neoplasia. 2009 May;11(5):485-96.
PMID 19412433
A feedback loop between BEX2 and ErbB2 mediated by c-Jun signaling in breast cancer.
Naderi A, Liu J, Francis GD.
Int J Cancer. 2012 Jan 1;130(1):71-82. doi: 10.1002/ijc.25977. Epub 2011 Apr 20.
PMID 21384344
Expression of BEX1 in acute myeloid leukemia with MLL rearrangements.
Quentmeier H, Tonelli R, Geffers R, Pession A, Uphoff CC, Drexler HG.
Leukemia. 2005 Aug;19(8):1488-9.
PMID 15920485
Hypomethylation and expression of BEX2, IGSF4 and TIMP3 indicative of MLL translocations in acute myeloid leukemia.
Rohrs S, Dirks WG, Meyer C, Marschalek R, Scherr M, Slany R, Wallace A, Drexler HG, Quentmeier H.
Mol Cancer. 2009 Oct 16;8:86.
PMID 19835597
Cloning and expression pattern of a spermatogenesis-related gene, BEX1, mapped to chromosome Xq22.
Yang QS, Xia F, Gu SH, Yuan HL, Chen JZ, Yang QS, Ying K, Xie Y, Mao YM.
Biochem Genet. 2002 Feb;40(1-2):1-12.
PMID 11989783


This paper should be referenced as such :
Lin, B ; Zhang, J ; Foltz, G
BEX2 (brain expressed X-linked 2)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(6):388-391.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)BEX2   30933
Entrez_Gene (NCBI)BEX2    brain expressed X-linked 2
AliasesBEX1; DJ79P11.1
GeneCards (Weizmann)BEX2
Ensembl hg19 (Hinxton)ENSG00000133134 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000133134 [Gene_View]  ENSG00000133134 [Sequence]  chrX:103309346-103310990 [Contig_View]  BEX2 [Vega]
ICGC DataPortalENSG00000133134
TCGA cBioPortalBEX2
AceView (NCBI)BEX2
Genatlas (Paris)BEX2
SOURCE (Princeton)BEX2
Genetics Home Reference (NIH)BEX2
Genomic and cartography
GoldenPath hg38 (UCSC)BEX2  -     chrX:103309346-103310990 -  Xq22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)BEX2  -     Xq22.2   [Description]    (hg19-Feb_2009)
GoldenPathBEX2 - Xq22.2 [CytoView hg19]  BEX2 - Xq22.2 [CytoView hg38]
genome Data Viewer NCBIBEX2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF251053 AK312085 AY833560 BC015522 BC050651
RefSeq transcript (Entrez)NM_001168399 NM_001168400 NM_001168401 NM_032621
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)BEX2
Alternative Splicing GalleryENSG00000133134
Gene ExpressionBEX2 [ NCBI-GEO ]   BEX2 [ EBI - ARRAY_EXPRESS ]   BEX2 [ SEEK ]   BEX2 [ MEM ]
Gene Expression Viewer (FireBrowse)BEX2 [ Firebrowse - Broad ]
GenevisibleExpression of BEX2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)84707
GTEX Portal (Tissue expression)BEX2
Human Protein AtlasENSG00000133134-BEX2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9BXY8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9BXY8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9BXY8
Splice isoforms : SwissVarQ9BXY8
Domains : Interpro (EBI)BEX    TF_A-like/BEX   
Domain families : Pfam (Sanger)BEX (PF04538)   
Domain families : Pfam (NCBI)pfam04538   
Conserved Domain (NCBI)BEX2
Blocks (Seattle)BEX2
Human Protein Atlas [tissue]ENSG00000133134-BEX2 [tissue]
Peptide AtlasQ9BXY8
IPIIPI00013250   IPI00955037   IPI00955017   IPI00647144   
Protein Interaction databases
IntAct (EBI)Q9BXY8
Ontologies - Pathways
Ontology : AmiGOsignaling receptor binding  protein binding  nucleus  cytoplasm  apoptotic process  cell cycle  signal transduction  regulation of apoptotic process  regulation of apoptotic process  regulation of cell cycle  
Ontology : EGO-EBIsignaling receptor binding  protein binding  nucleus  cytoplasm  apoptotic process  cell cycle  signal transduction  regulation of apoptotic process  regulation of apoptotic process  regulation of cell cycle  
NDEx NetworkBEX2
Atlas of Cancer Signalling NetworkBEX2
Wikipedia pathwaysBEX2
Orthology - Evolution
GeneTree (enSembl)ENSG00000133134
Phylogenetic Trees/Animal Genes : TreeFamBEX2
Homologs : HomoloGeneBEX2
Homology/Alignments : Family Browser (UCSC)BEX2
Gene fusions - Rearrangements
Fusion : Fusion_HubBEX1--BEX2    DDX21--BEX2   
Fusion : QuiverBEX2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBEX2 [hg38]
Exome Variant ServerBEX2
GNOMAD BrowserENSG00000133134
Varsome BrowserBEX2
Genomic Variants (DGV)BEX2 [DGVbeta]
DECIPHERBEX2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBEX2 
ICGC Data PortalBEX2 
TCGA Data PortalBEX2 
Broad Tumor PortalBEX2
OASIS PortalBEX2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBEX2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DBEX2
Mutations and Diseases : HGMDBEX2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)X-chromosome gene database
BioMutasearch BEX2
DgiDB (Drug Gene Interaction Database)BEX2
DoCM (Curated mutations)BEX2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BEX2 (select a term)
NCG6 (London) select BEX2
Cancer3DBEX2(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry BEX2
NextProtQ9BXY8 [Medical]
Target ValidationBEX2
Huge Navigator BEX2 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTD
Pharm GKB GenePA134977614
Clinical trialBEX2
canSAR (ICR)BEX2 (select the gene name)
DataMed IndexBEX2
PubMed28 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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