HGNC Approved Gene Symbol: BEX2
Cytogenetic location: Xq22.2 Genomic coordinates (GRCh38): X:103,309,346-103,310,990 (from NCBI)
Yang et al. (2002) identified a human paralog of the Bex1 (300690) mouse gene by high-throughput sequencing of a human fetal brain cDNA library. Although Yang et al. (2002) designated the gene BEX1, the deduced 125-amino acid protein showed highest sequence identity with mouse Bex2 (72%), and 68% and 36% sequence identity with mouse Bex1 and Bex3 (300361), respectively. The gene was later designated BEX2 by Alvarez et al. (2005). By Northern blot analysis of multiple human tissues, Yang et al. (2002) detected 2 BEX2 transcripts, of 1.3 kb and 1.0 kb. The 1.0-kb transcript was highly expressed in brain, pancreas, testis, and ovary, with lower levels present in heart, placenta, liver, kidney, spleen, thymus, prostate, small intestine, colon, thyroid, spinal cord, and adrenal gland. No hybridization was observed in lung, skeletal muscle, peripheral blood leukocyte, stomach, lymph node, trachea, or bone marrow.
Using a multiple human tissues array containing RNA from 75 human adult and fetal tissues and cancer cells line, Alvarez et al. (2005) found that BEX1 and BEX2 are expressed throughout the central nervous system, with high levels in pituitary, cerebellum, and temporal lobe. BEX2 is primarily expressed in brain, with lowest levels in cancer cell lines and throughout most of the gastrointestinal system. Mouse Bex2 was localized in both the nucleus and cytoplasm. Alvarez et al. (2005) showed that, unlike rat Bex3, rat Bex2 is not degraded by the proteasome.
Using a yeast 2-hybrid system with a human fetal brain cDNA library, Han et al. (2005) found that LMO2 (180385) interacted with human BEX2, but not with mouse Bex1 or Bex2. Protein pull-down and coimmunoprecipitation assays confirmed the interaction between LMO2 and BEX2. Electrophoretic mobility shift assays showed that BEX2 and LMO2 were part of a DNA-binding complex that recognized the E-box element. Other components of this complex included NSCL2 (NHLH2; 162361) and LDB1 (603451). LMO2 directly bound NSCL2 and upregulated NSCL2-dependent transcriptional activity, and BEX2 augmented this effect.
Foltz et al. (2006) treated human glioma cell lines with trichostatin A and 5-aza-2-prime-deoxycytidine to reverse promoter hypermethylation and histone deacetylation, and then used whole genome microarray analysis to identify tumor suppressor genes involved in human glioma. One of the genes they identified was BEX2, the expression of which was silenced in the 2 immortalized glioma cell lines and 10 primary glioma cells lines that were studied. Reactivation of BEX2 in these cell lines by TSA and 5-azaC treatment was confirmed by real-time PCR. Bisulfite sequence analysis of the CpG island in the promoter region of BEX2 showed that it is heavily methylated in glioma cell lines. Malignant glioma cell lines transfected with adenoviral BEX2 constructs showed a marked decrease in colony formation compared with control cells. There was no increase in the number of apoptotic cells after transfection with BEX2. However, in transfected cells treated with low doses of chemotherapeutic agents, there was a striking increase in the number of cells undergoing apoptosis. In nude mice injected with glioma cell lines, tumor growth was markedly decreased if the cells were transfected with BEX2. Similar results were obtained for BEX1.
By microarray analysis of 135 primary breast tumors, Naderi et al. (2007) identified a subset of estrogen receptor (ER, or ESR1; 133430)-positive cancers that overexpressed BEX1 and BEX2. Estrogen treatment induced expression of BEX2, but not BEX1, in an ER-positive breast cancer cell line. BEX2 expression was necessary and sufficient for NGF (see 162030)-mediated inhibition of apoptosis induced by a ceramide homolog, and BEX2 mediated NF-kappa-B (see 164011) activation in the NGF antiapoptotic pathway. BEX2 modulated apoptosis in breast cancer cells in response to estrogen and tamoxifen, and BEX2 overexpression enhanced the antiproliferative effect of a pharmacologic dose of tamoxifen.
Yang et al. (2002) stated that the BEX2 gene contains 3 exons and spans 15.5-bp genomic DNA, with an upstream CpG island but no TATA or CCAAT box in the promoter region.
Using radiation hybrid mapping, Yang et al. (2002) localized the BEX2 gene to human chromosome Xq22.
Alvarez, E., Zhou, W., Witta, S. E., Freed, C. R. Characterization of the Bex gene family in humans, mice, and rats. Gene 357: 18-28, 2005. [PubMed: 15958283] [Full Text: https://doi.org/10.1016/j.gene.2005.05.012]
Foltz, G., Ryu, G.-Y., Yoon, J.-G., Nelson, T., Fahey, J., Frakes, A., Lee, H., Field, L., Zander, K., Sibenaller, Z., Ryken, T. C., Vibhakar, R., Hood, L., Madan, A. Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res. 66: 6665-6674, 2006. [PubMed: 16818640] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-4453]
Han, C., Liu, H., Liu, J., Yin, K., Xie, Y., Shen, X., Wang, Y., Yuan, J., Qiang, B., Liu, Y.-J., Peng, X. Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex. Nucleic Acids Res. 33: 6555-6565, 2005. [PubMed: 16314316] [Full Text: https://doi.org/10.1093/nar/gki964]
Naderi, A., Teschendorff, A. E., Beigel, J., Cariati, M., Ellis, I. O., Brenton, J. D., Caldas, C. BEX2 is overexpressed in a subset of primary breast cancers and mediates nerve growth factor/nuclear factor-kappa-B inhibition of apoptosis in breast cancer cell lines. Cancer Res. 67: 6725-6736, 2007. [PubMed: 17638883] [Full Text: https://doi.org/10.1158/0008-5472.CAN-06-4394]
Yang, Q.-S., Xia, F., Gu, S.-H., Yuan, H.-L., Chen, J.-Z., Yang, Q.-S., Ying, K., Xie, Y., Mao, Y.-M. Cloning and expression pattern of a spermatogenesis-related gene, BEX1, mapped to chromosome Xq22. Biochem. Genet. 40: 1-12, 2002. [PubMed: 11989783] [Full Text: https://doi.org/10.1023/a:1014565320998]