Disease relevance of Runx3

• Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons [1].
• Since Runxl and Runx3 are involved in the development of some cancers including acute leukemia and gastric cancer, it will be of interest to examine in detail whether TGF-beta-specific R-Smads and Runx proteins coordinately regulate growth and differentiation of hematopoietic cells and gastric epithelial cells [2].
• Overexpression of Runx3 in mice increased germ-line alpha (GLalpha) transcription, and transcription was further augmented when B lymphoma and LPS-activated murine spleen cells were co-transfected with Smad3/4 [3].
• Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells [4].
• Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion [5].

High impact information on Runx3

• Runx3-deficient cytotoxic T cells, but not helper cells, have defective responses to antigen, suggesting that Runx proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes [6].
• We found that chondrocyte differentiation was inhibited depending on the dosages of Runx2 and Runx3, and Runx2(-/-)3(-/-) mice showed a complete absence of chondrocyte maturation [7].
• With CD27 to distinguish pre- and postselection DN3 cells, a detailed gene expression analysis defined regulatory changes associated with checkpoint arrest, with beta selection, and with gammadelta selection. gammadelta selection induces higher CD5, Egr, and Runx3 expression as compared to beta selection, but it triggers less proliferation [8].
• Among Runx family members, Runx3 expression was initiated in DP thymocytes receiving a positive selection signal and increased in concert with differentiation to the CD8SP stage [9].
• TOX-mediated positive selection is associated with up-regulation of Runx3, implicating CD4 silencing in the process [10].

Chemical compound and disease context of Runx3

• Here we report that in three of four cell lines derived from N-methyl-N-nitrosourea-induced mouse glandular stomach carcinomas, Runx3 is silenced due to hypermethylation of CpG islands in the promoter region, as we also observed for human gastric cancer cells [11].

Biological context of Runx3

• Comparison with the syntenic region of human chromosome 1 shows that the next gene is over 250 kb 5' to Runx3, suggesting that Runx3 may be the primary target of retroviral insertions at Dsi1 [12].
• Here, we describe the expression pattern of Runx3 during mouse embryogenesis compared to the expression pattern of Runx1 [13].
• However, Runx3 mutant mice did not show obvious tooth phenotype or deviations of Runx1 and Runx2 expression patterns in the tooth [14].
• In early tooth morphogenesis Runx3 was coexpressed with Runx2 in a thin layer of mesenchymal cells underlying dental epithelium [14].
• The human RUNX3/AML2 gene belongs to the 'runt domain' family of transcription factors that act as gene expression regulators in major developmental pathways [13].

Anatomical context of Runx3

• These differences between mutant upper and lower molars may be explained by the substitution of Runx2 function by Runx3, another member of the runt gene family that was upregulated in upper but not lower molars of Runx2 mutants [15].
• We found that Runx3 expression overlapped with that of Runx1 in the hematopoietic system, whereas in sensory ganglia, epidermal appendages, and developing skeletal elements, their expression was confined to different compartments [13].
• Runx3 is a runt-related transcription factor that acts as a gastric tumor suppressor and regulator of growth and differentiation in mammalian gastric epithelial cells [16].
• Unlike Runx2, Runx3 was expressed in odontoblasts [14].
• Here, we examined the expression of a downstream target of TGF-beta and BMPs, Runx3, in oral mucosa [16].

Associations of Runx3 with chemical compounds

• In this study we have investigated the role of Runx3 during thymocyte development and CD4 silencing and have identified integrin alpha(E)/CD103 on CD8 SP T cells as a new potential target gene of Runx3 [17].
• Although two of the sites we tested in the promoter of the fourth line were not methylated, in all four cases the silencing of Runx3 could be reversed by treatment of the cells with 5'-azacytidine and trichostatin A [11].

Physical interactions of Runx3

• This result was confirmed in cell culture, where full-length murine Runx1 and Runx3 both coprecipitated and colocalized with Pim-1 [18].

Regulatory relationships of Runx3

• Runx1 was expressed in several cartilage primordia earlier than Runx3, and Runx2 was intense in all mesenchymal condensations of bones and teeth [14].
• Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation [5].
• These results suggest that Runx3 positively regulates the expression of TrkC and TrkA in DRG neurons [19].

Other interactions of Runx3

• Runx1 and Runx3 are known to be involved in leukemogenesis and gastric carcinogenesis, respectively [20].
• Here we report that Runx3-deficient (Runx3(-/-)) mice displayed severe motor uncoordination and that few DRG neurons synthesized the proprioceptive neuronal marker parvalbumin [1].
• p300 cooperates with Smad3/4 and Runx3 in TGFbeta1-induced IgA isotype expression [3].
• Here we show that Runx3-/- mice display severe limb ataxia and abnormal posture and that most of them die shortly after birth [21].
• In Runx3-/- mouse gastric epithelium, Bim was down-regulated, and apoptosis was reduced to the same extent as that in Bim-/- gastric epithelium [22].

Analytical, diagnostic and therapeutic context of Runx3

• To analyze the role of runx genes in skeletal development, we performed in situ hybridization with Runx2- and Runx3-specific probes [23].
• E10.5 and E14.5-E16.5 embryos were analyzed using both immunohistochemistry and beta-galactosidase activity of targeted Runx3 and Runx1 loci [13].

References