Alternative titles; symbols
HGNC Approved Gene Symbol: MEOX2
Cytogenetic location: 7p21.2 Genomic coordinates (GRCh38): 7:15,611,212-15,686,683 (from NCBI)
Candia et al. (1992) isolated the mouse Mox2 gene, which belongs to a family of nonclustered, diverged homeobox genes. In situ hybridization analysis during murine embryogenesis indicated that the Mox2 gene is expressed in a wide range of mesodermal structures, including somites and vertebrae, the developing limbs, groups of muscles of the head, and the developing palate. These findings suggested that mutations in the human homolog of the Mox2 gene may be involved in craniofacial and/or skeletal abnormalities.
Gorski et al. (1993) isolated a clone corresponding to a homeoprotein gene from an adult rat aorta cDNA library, and termed it Gax, for 'growth arrest-specific homeobox,' to reflect the regulation of its expression in vascular smooth muscle cells. The deduced 303-amino acid protein contains a conserved homeodomain identical to that reported by Candia et al. (1992) for the Mox2 protein. Northern blot analysis detected a single mRNA transcript only in adult rat aorta smooth muscle cells, adult renal mesangial cells, and adult lung. Gax was more widely expressed in the developing cardiovascular system, multiple mesodermal tissues, and some ectodermal tissues.
LePage et al. (1994) isolated and characterized the human GAX gene. The human and rat GAX protein sequences showed 98% identity. Similar to the rat, the human homolog contains a CAX trinucleotide repeat N-terminal to the homeodomain that encodes a stretch of 17 consecutive histidine or glutamine residues.
Grigoriou et al. (1995) isolated and characterized cDNA clones for the human MOX2 gene. The MOX2 protein contains all of the characteristic features of Mox2 proteins of other vertebrate species, namely the homeobox, the polyhistidine stretch, and a number of potential serine/threonine phosphorylation sites. The homeodomain of the Mox2 protein is identical to that in all other vertebrate species studied to that time (rodents and amphibians).
By fluorescence in situ hybridization, LePage et al. (1994) mapped the human GAX gene to chromosome 7p22. Using the same method, Grigoriou et al. (1995) mapped the gene to 7p22.1-p21.3.
Gorski et al. (1993) mapped the mouse Gax gene to chromosome 12 by interspecific backcross analysis.
Gorski et al. (1993) found that expression of the GAX gene in vascular smooth muscle cells was rapidly downregulated when these cells were stimulated by mitogens to reenter the cell cycle. GAX expression was induced when proliferating cells were deprived of serum. The data suggested that GAX may have a regulatory role in the cell cycle.
Wu et al. (2005) cited reports suggesting that neurovascular dysfunction contributes to Alzheimer disease (AD; 104300), as manifest by altered cerebral blood flow, aberrant angiogenesis and vascular remodeling, and insufficient clearance of beta-amyloid. Using cDNA microarray analysis to examine human brain endothelial cells, Wu et al. (2005) found that expression of the MEOX2 gene was reduced in cells from 16 patients with Alzheimer disease compared to age-matched controls. Total capillary length in AD cortical brain tissue was reduced by approximately 60% compared to age-matched controls, and was inversely related to dementia scores. Transduction of the AD brain endothelial cells with the human MEOX2 gene increased vascular endothelial growth factor (VEGF; 192240)-mediated capillary tube formation and increased the levels of the low-density lipoprotein receptor-related protein-1 (LRP1; 107770), a major beta-amyloid clearance receptor at the blood-brain barrier. Partial deletion of the Meox gene in mice (Meox +/-) resulted in decreased brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain, and deficient clearance of beta-amyloid from the brain associated with from decreased levels of LRP1 at the blood-brain barrier. Wu et al. (2005) concluded that MEOX2 is linked to neurovascular dysfunction in AD.
Using a yeast 2-hybrid assay, Lin et al. (2005) found that MEOX2 had 11 putative interacting proteins, including RNF10 (615998). Using protein interaction assays, they confirmed a specific interaction between MEOX2 and RNF10. Domain analysis revealed that the C-terminal region of RNF10 interacted with a central region of MEOX2 between the histidine/glutamine-rich region and the homeodomain. Expression of RNF10 or MEOX2 in NIH-3T3 cells activated a p21(WAF1) (CDKN1A; 116899) reporter, and expression of both synergistically elevated reported activation.
Chen and Gorski (2008) identified 2 miR130A (MIRN130A; 610175) target sites within a 280-bp sequence of the GAX 3-prime UTR and showed that these sites were required for rapid downregulation of GAX expression by serum and proangiogenic factors in human umbilical vein endothelial cells. This 280-bp sequence of GAX mediated serum-induced downregulation of a reporter gene when ligated 3-prime of it. Conversely, forced expression of miR130A inhibited endogenous GAX expression.
Cao et al. (2010) found that MIR301 (MIR301A; 615675) indirectly upregulated expression of its host gene, SKA2. They determined that MIR301 inhibited expression of MEOX2, a negative regulator of the ERK/MAPK signaling pathway (see MAPK1, 176948) and downstream CREB (CREB1; 123810) phosphorylation, via 2 MIR301-binding sites in the MEOX2 3-prime UTR. Inhibitor, binding, and expression studies suggested that downregulation of MEOX2 via MIR301 first permitted ERK1 (MAPK3; 601795)/ERK2 (MAPK1) expression and activation, then CREB phosphorylation and binding of phosphorylated CREB to the SKA2 promoter, resulting in CREB-dependent induction of SKA2 expression.
Zhou et al. (2012) found that expression of MIR301A was significantly upregulated in hepatocellular carcinomas compared with matching normal tissues, concomitant with downregulation of GAX. Expression of an MIR301A inhibitor in HepG2 cells reduced cell proliferation, migration, and invasion and induced apoptosis, coincident with increased GAX mRNA expression.
The symbol MOX2 is used for a gene on chromosome 3 that encodes a membrane glycoprotein defined by a monoclonal antibody; see 155970.
Mankoo et al. (1999) generated mice homozygous for a null mutation of Mox2 by targeted disruption. Mox2 -/- mice had a developmental defect of the limb musculature characterized by an overall reduction in muscle mass and elimination of specific muscles. Mox2 was not needed for the migration of myogenic precursors into the limb bud, but it was essential for normal appendicular muscle formation and for the normal regulation of myogenic genes, as demonstrated by the downregulation of Pax3 (600535) and Myf5 (159990), but not MyoD (159970), in Mox2-deficient limb buds. Mankoo et al. (1999) concluded that MOX2 homeoprotein is an important regulator of vertebrate limb myogenesis.
Candia, A. F., Hu, J., Crosby, J., Lalley, P. A., Noden, D., Nadeau, J. H., Wright, C. V. E. Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos. Development 116: 1123-1136, 1992. [PubMed: 1363541] [Full Text: https://doi.org/10.1242/dev.116.4.1123]
Cao, G., Huang, B., Liu, Z., Zhang, J., Xu, H., Xia, W., Li, J., Li, S., Chen, L., Ding, H., Zhao, Q., Fan, M., Shen, B., Shao, N. Intronic miR-301 feedback regulates its host gene, ska2, in A549 cells by targeting MEOX2 to affect ERK/CREB pathways. Biochem. Biophys. Res. Commun. 396: 978-982, 2010. [PubMed: 20470754] [Full Text: https://doi.org/10.1016/j.bbrc.2010.05.037]
Chen, Y., Gorski, D. H. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood 111: 1217-1226, 2008. [PubMed: 17957028] [Full Text: https://doi.org/10.1182/blood-2007-07-104133]
Gorski, D. H., LePage, D. F., Patel, C. V., Copeland, N. G., Jenkins, N. A., Walsh, K. Molecular cloning of a diverged homeobox gene that is rapidly down-regulated during the G0/G1 transition in vascular smooth muscle cells. Molec. Cell. Biol. 13: 3722-3733, 1993. [PubMed: 8098844] [Full Text: https://doi.org/10.1128/mcb.13.6.3722-3733.1993]
Grigoriou, M., Kastrinaki, M.-C., Modi, W. S., Theodorakis, K., Mankoo, B., Pachnis, V., Karagogeos, D. Isolation of the human MOX2 homeobox gene and localization to chromosome 7p22.1-p21.3. Genomics 26: 550-555, 1995. [PubMed: 7607679] [Full Text: https://doi.org/10.1016/0888-7543(95)80174-k]
LePage, D. F., Altomare, D. A., Testa, J. R., Walsh, K. Molecular cloning and localization of the human GAX gene to 7p21. Genomics 24: 535-540, 1994. [PubMed: 7713505] [Full Text: https://doi.org/10.1006/geno.1994.1663]
Lin, J., Friesen, M. T., Bocangel, P., Cheung, D., Rawszer, K., Wigle, J. T. Characterization of mesenchyme homeobox 2 (MEOX2) transcription factor binding to RING finger protein 10. Molec. Cell. Biochem. 275: 75-84, 2005. [PubMed: 16335786] [Full Text: https://doi.org/10.1007/s11010-005-0823-3]
Mankoo, B. S., Collins, N. S., Ashby, P., Grigorievea, E., Pevny, L. H., Candia, A., Wright, C. V. E., Rigby, P. W. J., Pachnis, V. Mox2 is a component of the genetic hierarchy controlling limb muscle development. Nature 400: 69-73, 1999. [PubMed: 10403250] [Full Text: https://doi.org/10.1038/21892]
Wu, Z., Guo, H., Chow, N., Sallstrom, J., Bell, R. D., Deane, R., Brooks, A. I., Kanagala, S., Rubio, A., Sagare, A., Liu, D., Li, F., Armstrong, D., Gasiewicz, T., Zidovetzki, R., Song, X., Hofman, F., Zlokovic, B. V. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nature Med. 11: 959-965, 2005. [PubMed: 16116430] [Full Text: https://doi.org/10.1038/nm1287]
Zhou, P., Jiang, W., Wu, L., Chang, R., Wu, K., Wang, Z. miR-301a is a candidate oncogene that targets the homeobox gene Gax in human hepatocellular carcinoma. Dig. Dis. Sci. 57: 1171-1180, 2012. [PubMed: 22373864] [Full Text: https://doi.org/10.1007/s10620-012-2099-2]