HGNC Approved Gene Symbol: PBX3
Cytogenetic location: 9q33.3 Genomic coordinates (GRCh38): 9:125,747,373-125,967,377 (from NCBI)
PBX3 belongs to the conserved PBX family of TALE (3-amino acid loop extension) homeodomain transcription factors, which are implicated in developmental gene expression. PBX proteins form heterooligomeric DNA-binding complexes that regulate transcription in various cell types (summary by Rhee et al., 2004).
Monica et al. (1991) isolated 2 new homeobox genes, PBX2 (176311) and PBX3, on the basis of their extensive homology to PBX1 (176310). The predicted PBX2 and PBX3 proteins share 92% and 94% identity with PBX1 over a 266-amino acid region within and flanking their homeodomains, but all 3 proteins diverge significantly near their N and C termini. Unlike PBX1, which is not expressed in lymphoid cell lines, expression of PBX2 and PBX3 was not restricted to particular states of differentiation or development, as mRNA transcripts of these genes were detected in most fetal and adult tissues and all cell lines. Like PBX1 RNA, PBX3 RNA is alternatively spliced to yield 2 translation products with different carboxy termini, a feature not observed for PBX2. Their extensive sequence similarity and widespread expression suggest a generalized, overlapping role for PBX proteins in most cell types. Differences in their N and C termini may modulate their activities, mediated in part by differential splicing and, for PBX1, protein fusion following t(1;19) chromosomal translocation.
By PCR of an erythroleukemia cell line cDNA library, Milech et al. (2001) cloned 2 novel splice variants of PBX3 that they termed PBX3C and PBX3D. Both PBX3C and PBX3D encode N-terminally truncated isoforms that lack the PBC-A domain and most of the PBC-B domain of the PBX3A and PBX3B isoforms reported by Monica et al. (1991). RT-PCR detected expression of PBX3C and PBX3D in all cell lines and primary cells examined, including 17 leukemia cell lines. PBX3D showed higher expression than PBX3C in normal cells, whereas PBX3C showed higher expression in leukemia cells.
By immunohistochemical analysis, Rhee et al. (2004) detected expression of Pbx3 in central and peripheral nervous systems of mouse embryos.
Milech et al. (2001) determined that the PBX3 gene contains 9 exons, with exons 3 and 7 subject to alternative splicing.
Monica et al. (1991) mapped PBX3 to chromosome 9q33-q34 by in situ hybridization. Pilz et al. (1994) mapped the homologous gene to mouse chromosome 2.
As part of a study of a triplication of several megabases occurring on chromosomes 1, 6, and 9, Katsanis et al. (1996) confirmed the presence of a PBX locus on chromosome 9q34.
Milech et al. (2001) found that, in contrast with PBX3B, the PBX3C and PBX3D isoforms were unable to interact with PREP1 (PKNOX1; 602100) and interacted only weakly with MEIS1 (601739). Milech et al. (2001) proposed that PBX3C and PBX3D may affect PBX3-mediated transcriptional regulation by acting in opposition to other PBX proteins through alternative PBX3 complex formation.
Rhee et al. (2004) found that Pbx3 +/- mice were viable and fertile. In contrast, Pbx3 -/- mice died within hours after birth with apnea, cyanosis, and lack of lung inflation and ventilation, in spite of normal nerve structures in brain and spinal cord. Expression of Rnx (604640) and Meis1 was not affected in Pbx3 -/- mice, but Rnx was unable to enhance transcription as a complex with TALE proteins, such as Meis1, in the absence of Pbx3. Rhee et al. (2004) concluded that PBX3A and RNX, together with MEIS1, are essential for respiration and proper development of medullary respiratory control mechanisms. They suggested that Pbx3 or Rnx deficiency may model central hypoventilation syndrome (see 209880).
Katsanis, N., Fitzgibbon, J., Fisher, E. M. C. Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci. Genomics 35: 101-108, 1996. [PubMed: 8661110] [Full Text: https://doi.org/10.1006/geno.1996.0328]
Milech, N., Kees, U. R., Watt, P. M. Novel alternative PBX3 isoforms in leukemia cells with distinct interaction specificities. Genes Chromosomes Cancer 32: 275-280, 2001. [PubMed: 11579467] [Full Text: https://doi.org/10.1002/gcc.1190]
Monica, K., Galili, N., Nourse, J., Saltman, D., Cleary, M. L. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Molec. Cell. Biol. 11: 6149-6157, 1991. [PubMed: 1682799] [Full Text: https://doi.org/10.1128/mcb.11.12.6149-6157.1991]
Pilz, A., Prohaska, R., Peters, J., Abbott, C. Genetic linkage analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notch1 genes in the region of mouse chromosome 2 homologous to human chromosome 9q. Genomics 21: 104-109, 1994. [PubMed: 8088777] [Full Text: https://doi.org/10.1006/geno.1994.1230]
Rhee, J. W., Arata, A., Selleri, L., Jacobs, Y., Arata, S., Onimaru, H., Cleary, M. L. Pbx3 deficiency results in central hypoventilation. Am. J. Path. 165: 1343-1350, 2004. [PubMed: 15466398] [Full Text: https://doi.org/10.1016/S0002-9440(10)63392-5]