Download Gene Section BEX2 (brain expressed X-linked 2) Atlas of Genetics and Cytogenetics

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BEX2 (brain expressed X-linked 2)
Biaoyang Lin, Jing Zhang, Greg Foltz
Swedish Medical Center, Seattle, WA, USA; Zhejiang-California International NanoSystems Institute,
Zhejiang Univ Hangzhou, China (BL), Zhejiang-California International NanoSystems Institute, Zhejiang
Univ Hangzhou, China (JZ), Swedish Medical Center, Seattle, WA, USA (GF)
Published in Atlas Database: January 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/BEX2ID44162chXq22.html
DOI: 10.4267/2042/47335
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Identity
Other names: BEX1, DJ79P11.1
HGNC (Hugo): BEX2
Location: Xq22.1
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).
DNA/RNA
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.
Protein
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 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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Description
BEX2 has multiple protein isoforms. In one isoform
(NP_116010.1), it contains 128 amino acid residues.
388
BEX2 (brain expressed X-linked 2)
Lin B, et al.
A diagram using the UCSC genome browser showing the locations of the five BEX members in the order of BEX5-BEX1-BEX4-BEX2NGFRAP1 (nerve growth factor receptor (TNFRSF16) associated protein 1, BEX3) on the X chromosome at Xq22.1-2, along with other
genes in the region.
BEX3), BEX4, and BEX5. They are all clustered on the
X chromosome at Xq22.1-2 (Alvarez et al., 2005).
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).
Mutations
Note
None identified.
Implicated in
Glioma
Note
We showed that BEX1 and BEX2 are candidate tumor
suppressor genes in malignant glioma in a genomewide 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 (5AzaC), 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
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,
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
389
BEX2 (brain expressed X-linked 2)
Lin B, et al.
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.
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.
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.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
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This article should be referenced as such:
Lin B, Zhang J, Foltz G. BEX2 (brain expressed X-linked 2).
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Naderi A, Liu J, Bennett IC. BEX2 regulates mitochondrial
apoptosis and G1 cell cycle in breast cancer. Int J Cancer.
2010a Apr 1;126(7):1596-610
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