Alternative titles; symbols
HGNC Approved Gene Symbol: RUNX3
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:24,899,511-24,965,138 (from NCBI)
The RUNX3 gene encodes a Runt-related transcription factor, which is part of the RUNX gene family (see RUNX1, 151385 and RUNX2, 600211). The RUNX transcription factors are composed of an alpha subunit, encoded by the RUNX1, RUNX2, and RUNX3 genes, which binds to DNA via a Runt domain, and a beta subunit, encoded by the CBFB gene (121360), which increases the affinity of the alpha subunit for DNA but shows no DNA binding by itself. These proteins have a conserved 128-amino acid Runt domain, so called because of its homology to the pair-rule gene runt, which plays a role in the segmented body patterning of Drosophila. RUNX3 is required for CD8 T-cell development during thymopoiesis; has a primary role in determining the dorsoventral projection pattern of proprioceptive and cutaneous sensory neurons; has a role in bone formation; is found in mesenchymal elements of epidermal appendages; and controls the proper development of gastric endothelial cells by apoptosis. It also acts as a tumor suppressor gene (review by Cohen, 2009).
Levanon et al. (1994) isolated and characterized cDNAs corresponding to 3 human runt domain-containing genes: AML1 (RUNX1; 151385), CBFA3, and CBFA1 (RUNX2; 600211). In addition to homology in the highly conserved runt domain, extensive sequence similarities were also observed in other parts of the deduced proteins. All 3 genes carried an identical putative ATP-binding site, GRSGRGKS, and their C-terminal halves were particularly rich in proline and serine residues. AML1 cDNAs had been cloned by others, whereas CBFA3 represented a novel member of the runt domain gene family, and CBFA1 was identified as the human homolog of the mouse PEBP2A gene.
Bae et al. (1995) also cloned and characterized RUNX3, which they termed PEBP2-alpha-C.
By genomic sequence analysis, Bae et al. (1995) determined that the RUNX3 gene contains at least 5 exons.
Cohen (2009) stated that RUNX3 is the smallest of the RUNX genes, with 6 exons and very few isoforms.
Taniuchi et al. (2002) showed that binding sites for Runt domain transcription factors are essential for CD4 (186940) transcriptional silencer function, and that different RUNX family members are required to fulfill unique functions at each stage. They found that RUNX1 is required for active repression in CD4-negative/CD8 (see 186910)-negative thymocytes, whereas RUNX3 is required for establishing epigenetic silencing in cytotoxic lineage thymocytes. Cytotoxic T cells deficient in Runx3, but not helper cells, had defective responses to antigen, suggesting that RUNX proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes.
Stein et al. (2004) reviewed the function of mammalian Runx proteins in osteogenesis. They stated that Runx2 is the principal osteogenic master switch, while Runx1 and Runx3 are expressed in bone cells and appear to support bone cell development and differentiation.
Using immunohistochemistry and RNA in situ hybridization in mice, Brenner et al. (2004) detected Runx3 expression in the gastrointestinal tract in lymphoid and myeloid populations but not in the epithelium.
Xu et al. (2016) found that overexpression of microRNA532-5p (MIR532; 301023) promoted growth of human gastric cancer (GC) cells by promoting cell cycle progression and cell migration and inhibiting apoptosis. In vivo analysis with mice showed that MIR532-5p triggered GC cell invasion from veins to lungs and strengthened GC cell colonization and growth in mouse lungs. Bioinformatic analysis identified RUNX3 as a putative target of MIR532-5p. Overexpression and knockdown studies in GC cells and luciferase reporter assays demonstrated that MIR532-5p negatively regulated RUNX3 expression at the transcriptional and translational levels by directly targeting RUNX3 mRNA.
Milner et al. (2017) identified the transcription factor RUNX3 as a key regulator of tissue-resident memory CD8+ T (TRM) cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, Milner et al. (2017) showed that human and mouse tumor-infiltrating lymphocytes share a core tissue-residency gene expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumor-infiltrating lymphocytes failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced tumor-specific CD8+ T cell abundance, delayed tumor growth, and prolonged survival.
By fluorescence in situ hybridization, Levanon et al. (1994) mapped the CBFA3 gene to 1p36. By FISH, Bae et al. (1995) mapped the RUNX3 gene to 1p36.13-p36.11. Avraham et al. (1995) mapped the homologous gene to mouse chromosome 4. By Southern blot analysis of hybrid cell lines containing different parts of human chromosome 1 and by fluorescence in situ hybridization, Wijmenga et al. (1995) assigned the CBFA3 gene to 1pter-p35.
Li et al. (2002) showed that between 45 and 60% of human gastric cancer (see 133239) cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression. The authors identified a heterozygous C-to-T transition in the RUNX3 gene, resulting in an arg122-to-cys (R122C) change within the conserved Runt domain of the protein, in 1 gastric carcinoma tissue of 119 examined. Arginine at position 122 is conserved in both nematodes and humans. A tumorigenesis assay in nude mice showed that the R122C change abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. However, matching normal tissue was not available in this case and therefore it was not possible to establish whether the observed R122C change was a single-nucleotide polymorphism or a true mutation.
In 86 samples from gastric tumors, Wei et al. (2005) found a loss or substantial decrease of RUNX3 protein expression compared to normal gastric mucosa (p less than 0.0001). Decreased RUNX3 expression was significantly associated with decreased survival (p = 0.0005). Studies in gastric cancer cell lines also showed loss or decreased RUNX3 expression, and restoration of RUNX3 induced cell cycle arrest and apoptosis, resulting in suppression of cancer cell growth. Restoration of RUNX3 led to downregulation of cyclin D1 (CCND1; 168461) and upregulation of p27 (CDKN1B; 600778), CASP3 (600636), CASP7 (601761), and CASP8 (601763). RUNX3-transduced gastric cancer cells showed poor growth compared to nontransduced cells when injected into mice. The findings implicated RUNX3 as a tumor suppressor gene in gastric cancer.
Ito et al. (2005) demonstrated RUNX3 immunostaining in almost all normal stomach epithelial cells. Chief cells and surface epithelial cells stained most strongly, whereas parietal cells showed a lower level of expression. RUNX3 staining was mostly in the cell nucleus, although some cytoplasmic staining was also observed. RUNX3 was not detected in 43 (44%) of 97 gastric tumors analyzed, and 37 (38%) 97 tumors showed exclusive cytoplasmic localization of RUNX3. Only 17 (18%) of 97 tumors showed normal nuclear localization. TGF-beta (TGFB1; 190180) was identified as an agent that stimulated the translocation of RUNX3 from the cytoplasm to the nucleus, where it can act as a transcription factor. Studies in gastric cell lines indicated that RUNX3 is required for TGFB-dependent growth inhibition. Cytoplasmic retention of RUNX3 in gastric cancer cells indicated that it is inactivated as a tumor suppressor by mislocalization. The findings also suggested impairment of the TGF-beta signaling pathway in gastric cancer.
Li et al. (2002) generated mice with a targeted disruption of the Runx3 gene. The gastric mucosa of these mice exhibited hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells were resistant to growth-inhibitory and apoptosis-inducing actions of Tgfb, indicating that Runx3 is a major growth regulator of gastric epithelial cells.
Inoue et al. (2002) generated Runx3-deficient mice and showed that proprioceptive afferent axons failed to project to their targets in the spinal cord as well as those in the muscle. In contrast, the afferent projections that convey nociception, thermoreception, and mechanoreception signals appeared normal. The mutant mice displayed severe limb ataxia and motor discoordination similar to that of Etv1 (600541) mutant mice. Inoue et al. (2002) concluded that Runx3 is critical in regulating a subpopulation of dorsal root ganglion neurons.
Yoshida et al. (2004) presented evidence that Runx3 and Runx2 are involved in chondrocyte proliferation and maturation during skeletal development. Runx2/Runx3 double-knockout mice displayed a complete absence of chondrocyte differentiation, and the residual expression of the chondrocyte-specific transcription factor Ihh (600726) found in Runx2 knockout mice was absent in double-knockout mice. Single- or double-heterozygous mice showed intermediate degrees of chondrocyte differentiation depending upon the dosages of Runx2 and Runx3 expressed. Limb length was also reduced depending on the dosages of Runx2 and Runx3.
To elucidate the function of RUNX3, Fukamachi and Ito (2004) generated mice lacking the gene and examined its role in their development. The Runx3 knockout mice died soon after birth. Gastric epithelia exhibited hyperplasia and epithelial apoptosis was suppressed. Analysis using a primary culture system for the epithelial cells suggested that this was caused by reduced sensitivity of the Runx3-null gastric epithelial cells to the growth-inhibiting and apoptosis-inducing activities of Tgfb. The results suggested that RUNX3 is a major growth regulator of gastric epithelial cells, and may be deeply involved in gastric tumorigenesis in both humans and mice.
Fainaru et al. (2004) found that Runx3 is highly expressed in mouse dendritic cells (DCs), where it functions as a component of the Tgf-beta (153440) signaling cascade. Runx3 knockout caused loss of Langerhans cells, accelerated maturation of DC, increased stimulation of T cells, and aberrant expression of beta-2 integrins (see 135630). Runx3-null mice developed spontaneous eosinophilic lung inflammation, indicating an overresponse to otherwise innocuous airborne antigens. Fainaru et al. (2004) noted that the human RUNX3 gene resides in a region of chromosome 1p36.1 that contains susceptibility genes for asthma and hypersensitivity against environmental antigens, and they hypothesized that RUNX3 deficiency may constitute an asthma risk factor in humans.
Using flow cytometry, Fainaru et al. (2005) found that Runx3 -/- mice had dysregulated expression of Ccr7 (600242), resulting in accelerated trafficking of DCs from airways to regional lymph nodes. They showed that loss of Runx3 led to loss of Tgfb-mediated transcription attenuation of Ccr7. Runx3 -/- mice spontaneously developed asthma-like features, including airway hyperresponsiveness, increased serum IgE, and hypersensitivity to lipopolysaccharide.
In Runx3 -/- mice, Brenner et al. (2004) observed the spontaneous development of inflammatory bowel disease (see IBD; 266600) at 4 weeks of age, with leukocyte infiltration, mucosal hyperplasia, formation of lymphoid clusters, and increased production of IgA. At 8 months of age, the null mice also developed progressive hyperplasia of the gastric mucosa with disturbed epithelial differentiation and cellular hyaline degeneration. In wildtype mice, Runx3 expression was detected in lymphoid and myeloid populations but not the epithelium. Brenner et al. (2004) concluded that loss of leukocyte cell-autonomous function of Runx3 results in inflammatory bowel disease and gastric lesions in the null mice.
Avraham, K. B., Levanon, D., Negreanu, V., Bernstein, Y., Groner, Y., Copeland, N. G., Jenkins, N. A. Mapping of the mouse homolog of the human runt domain gene, AML2, to the distal region of mouse chromosome 4. Genomics 25: 603-605, 1995. [PubMed: 7790005] [Full Text: https://doi.org/10.1016/0888-7543(95)80073-u]
Bae, S.-C., Takahashi, E., Zhang, Y. W., Ogawa, E., Shigesada, K., Namba, Y., Satake, M., Ito, Y. Cloning, mapping and expression of PEBP2-alpha-C, a third gene encoding the mammalian Runt domain. Gene 159: 245-248, 1995. [PubMed: 7622058] [Full Text: https://doi.org/10.1016/0378-1119(95)00060-j]
Brenner, O., Levanon, D., Negreanu, V., Golubkov, O., Fainaru, O., Woolf, E., Groner, Y. Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc. Nat. Acad. Sci. 101: 16016-16021, 2004. [PubMed: 15514019] [Full Text: https://doi.org/10.1073/pnas.0407180101]
Cohen, M. M., Jr. Perspectives on RUNX genes: an update. Am. J. Med. Genet. 149A: 2629-2646, 2009. [PubMed: 19830829] [Full Text: https://doi.org/10.1002/ajmg.a.33021]
Fainaru, O., Shseyov, D., Hantisteanu, S., Groner, Y. Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease. Proc. Nat. Acad. Sci. 102: 10598-10603, 2005. [PubMed: 16027362] [Full Text: https://doi.org/10.1073/pnas.0504787102]
Fainaru, O., Woolf, E., Lotem, J., Yarmus, M., Brenner, O., Goldenberg, D., Negreanu, V., Bernstein, Y., Levanon, D., Jung, S., Groner, Y. Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 23: 969-979, 2004. [PubMed: 14765120] [Full Text: https://doi.org/10.1038/sj.emboj.7600085]
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Inoue, K,, Ozaki, S., Shiga, T., Ito, K., Masuda, T., Okado, N., Iseda, T., Kawaguchi, S., Ogawa, M., Bae, S.-C., Yamashita, N., Itohara, S., Kudo, N., Ito, Y. Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nature Neurosci. 5: 946-954, 2002. [PubMed: 12352981] [Full Text: https://doi.org/10.1038/nn925]
Ito, K., Liu, Q., Salto-Tellez, M., Yano, T., Tada, K., Ida, H., Huang, C., Shah, N., Inoue, M., Rajnakova, A., Hiong, K. C., Peh, B. K., Han, H. C., Ito, T., Teh, M., Yeoh, K. G., Ito, Y. RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res. 65: 7743-7750, 2005. Note: Erratum: Cancer Res. 66: 3345 only, 2006. [PubMed: 16140942] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-0743]
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Li, Q.-L., Ito, K., Sakakura, C., Fukamachi, H., Inoue, K., Chi, X.-Z., Lee, K.-Y., Nomura, S., Lee, C.-W., Han, S.-B., Kim, H.-M., Kim, W.-J., and 15 others. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109: 113-124, 2002. [PubMed: 11955451] [Full Text: https://doi.org/10.1016/s0092-8674(02)00690-6]
Milner, J. J., Toma, C., Yu, B., Zhang, K., Omilusik, K., Phan, A. T., Wang, D., Getzler, A. J., Nguyen, T., Crotty, S., Wang, W., Pipkin, M. E., Goldrath, A. W. Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 552: 253-257, 2017. Note: Erratum: Nature 554: 392 only, 2018. [PubMed: 29211713] [Full Text: https://doi.org/10.1038/nature24993]
Stein, G. S., Lian, J. B., van Wijnen, A. J., Stein, J. L., Montecino, M., Javed, A., Zaidi, S. K., Young, D. W., Choi, J.-Y., Pockwinse, S. M. Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene 23: 4315-4329, 2004. [PubMed: 15156188] [Full Text: https://doi.org/10.1038/sj.onc.1207676]
Taniuchi, I., Osato, M., Egawa, T., Sunshine, M. J., Bae, S.-C., Komori, T., Ito, Y., Littman, D. R. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111: 621-633, 2002. [PubMed: 12464175] [Full Text: https://doi.org/10.1016/s0092-8674(02)01111-x]
Wei, D., Gong, W., Oh, S. C., Li, Q., Kim, W. D., Wang, L., Le, X., Yao, J., Wu, T. T., Huang, S., Xie, K. Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis. Cancer Res. 65: 4809-4816, 2005. [PubMed: 15930301] [Full Text: https://doi.org/10.1158/0008-5472.CAN-04-3741]
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Xu, X., Zhang, Y., Liu, Z., Zhang, X., Jia, J. miRNA-532-5p functions as an oncogenic microRNA in human gastric cancer by directly targeting RUNX3. J. Cell. Molec. Med. 20: 95-103, 2016. [PubMed: 26515139] [Full Text: https://doi.org/10.1111/jcmm.12706]
Yoshida, C. A., Yamamoto, H., Fujita, T., Furuichi, T., Ito, K., Inoue, K., Yamana, K., Zanma, A., Takada, K., Ito, Y., Komori, T. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev. 18: 952-963, 2004. [PubMed: 15107406] [Full Text: https://doi.org/10.1101/gad.1174704]