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FLASH GENE
Symbol RUNX3 contributors: mct - updated : 24-03-2017
HGNC name runt-related transcription factor 3
HGNC id 10473
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N terminal alanine and glutamine stretch
  • a C terminal Runt domain, and a proline/serine/threonine rich region necessary for transcriptional activation of target genes
  • a DNA-binding motif with an Ig-like protein fold, related to the DNA-binding domain of TP53
  • a nuclear matrix signal
  • a putative ATP binding site
  • a transactivation domain localization
    • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to Drosophila Runt pair rule-related transcription factor
    Homologene
    FAMILY
  • runt domain gene family
    • CATEGORY regulatory , DNA associated , transcription factor , tumor suppressor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    intracellular,nucleus,nucleolus
    text can be inactivated by the mislocalization of the protein in the cytoplasm through overexpression of SRC
    basic FUNCTION
  • involved in hematopoiesis and osteogenesis
  • required for differentiation of functional cytotoxic T cells and for CD4 silencing
  • playing a role in the pathogenesis of primary and metastatic pancreatic ductal adenocarcinoma
  • universal downstream mediator of a constitutively active Shh pathway in basal cell carcinomas
  • essential for mediating the early stage of endochondral ossification through cooperation with other RUNX family members
  • playing a role in mediating stage-specific chondrocyte maturation
  • target for repression by EZH2 and indicated an underlying mechanism of the functional role of EZH2 overexpression on cancer cell proliferation
  • potential role of the STAT5B-RUNX interaction in lymphocyte development
  • involved in TGF-beta-dependent and -independent cell growth inhibition and apoptosis induction pathways
  • acting as a novel co-activator for TP53 through regulating its DNA damage-induced phosphorylation
  • having a tumor suppressive role, but can also function as an oncogene when overexpressed
  • involved in a variety of physiological processes including neurogenesis, thymopoiesis, and dendritic cell maturation
  • induction of RUNX3 may be a mechanism to maintain NOTCH1-transformed mesenchymal cells during heart development
  • RUNX1 and RUNX3 play crucial roles in dorsal root ganglion neurogenesis
  • role for RUNX3 as a tumor suppressor in neuroblastoma
  • regulates intercellular adhesion molecule 3 (ICAM3) expression during macrophage differentiation and monocyte extravasation
  • reverses epithelial-mesenchymal transition in hepatocellular carcinoma
  • protective role for RUNX3 in safeguarding gastric epithelial cells against aberrant growth factor signaling and the resultant cellular plasticity and stemness
  • acts to regulate positional differences in axon extension properties apparently without affecting nerve guidance and branching, a principle that could be relevant to other parts of the nervous system
  • RUNX1 and RUNX3 are involved in the generation and function of highly suppressive IL17-producing T regulatory cells
  • like RUNX3, RUNX1 plays a pivotal role in the regulation of apoptosis in response to a wide variety of cellular pro-apoptotic stimuli such as DNA damage and TGFB1
  • RUNX3 positively regulates aggrecan expression, suggesting that its function is more limited to cartilage development than to bone
  • both RUNX2 and RUNX3 mRNAs were differentially up regulated during fracture healing
  • role of RUNX3 in CD8(+) T and NK activated cells
  • is essential for normal vertebrate lung development
  • might be involved in human bone mineralization
  • does play important functions in immunity and inflammation and may thereby indirectly influence epithelial tumor development
  • plays an important role in the regulation of T cell differentiation into Th1 cells
  • is a key transcription factor in the lineage-specific differentiation of ILC1 and ILC3 cells
  • RUNX1 and RUNX3 maintain genomic integrity in a transcriptional manner by regulating the transactivation of apoptotic genes following DNA damage via complex formation with TP53
    • CELLULAR PROCESS cell life, differentiation
    nucleotide, transcription
    PHYSIOLOGICAL PROCESS development
    text growth regulator of gastric epithelial cells
    PATHWAY
    metabolism
    signaling
    TGF-beta, LMO1, possibly RUNX3, and GSDM form a regulatory pathway for directing the pit cells to apoptosis
    a component
  • heterodimer of an alpha and a beta subunit (CBFB)
  • the alpha subunit binds DNA as a monomer and
    • through the Runt domain
  • important component of the transforming growth factor-beta (TGFB)-induced tumor suppression pathway (
    • INTERACTION
    DNA DNA-binding is increased by heterodimerization
    RNA
    small molecule
    protein
  • SMAD (MADHs) genes, signal transducers of the TGFBR-BMP pathway
  • interacting with TLE1
  • interacting with CDKN1A (tumor suppressor activity of RUNX3 is associated with its ability to induce CDKN1A expression)
  • transcriptionally inhibits RUNX1 expression in chondrocytes
  • may cooperate with RUNX2 to induce chondrocyte terminal differentiation, and inhibits RUNX1 expression during late maturation
  • interaction with RUNX1 (repression of RUNX1 by RUNX3 is required to allow the cell proliferation and this provides an experimental system to investigate the mechanism of the different activities of RUNX1 and RUNX3 in these cells)
  • association between EZH2 bound to the RUNX3 gene promoter, and trimethylated histone H3 at lysine 27, and HDAC1 (histone deacetylase 1) bound to the RUNX3 gene promoter in cancer cells
  • interacting with STAT5B (inhibits the nuclear localization of RUNX proteins and retains them in the cytoplasm)
  • ZFHX3 associates with RUNX3 and translocates to the nucleus in response to TGF-beta signal transduction and might function in the nucleus as tumor suppressor and transcriptional regulator
  • CCND1–RUNX3 interaction interferes with the RUNX3–EP300 interaction, leading to the inhibition of transcriptional activation by RUNX3, downregulation of CDKN1A expression, and the blocking of the RUNX3-dependent inhibition of cancer cell proliferation
  • interacting with CXCL12 (CXCL12 autocrine/paracrine signaling down-regulates the expression of the transcription factor RUNX3 and contributes to maintain the long-term CD4 and CD14 expression in monocytes/macrophages)
  • direct target gene of NOTCH1 in endothelial cells and may play a role in sustaining the mesenchymal phenotype in cardiac cushion cells during heart development
  • inhibits ESR1-dependent transactivation by reducing the stability of ESR1
  • by destabilizing ESR1, RUNX3 acts as a novel tumor suppressor in breast cancer
  • ICAM3 is negatively regulated by RUNX1, RUNX3
  • binding of PIN1 to RUNX3 suppresses the transcriptional activity of RUNX3
  • TWIST1 regulation of IFNG depends on complex formation with RUNX3
  • induced to access the cell nucleus following DNA damage and formed a complex with TP53 to enhance its transcriptional as well as pro-apoptotic activity
  • IL23A is a RUNX3 target gene in gastric epithelial cells
  • cooperation between the transcription factors TBX21 and RUNX3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program
  • NR4A1 is a novel and critical player in the regulation of CD8 T cell development through the direct suppression of RUNX3
  • may play a crucial role in the development of Dorsal root ganglion (DRG) by regulating the expression of NTRK3 variants
  • NTRK2 plays a key role in regulation of the tumor suppressors RUNX3 and KEAP1
  • RUNX1 and RUNX3 also maintain genomic integrity in a non-transcriptional manner during interstand crosslink repair by promoting the recruitment of FANCD2 to sites of DNA damage
    • cell & other
    REGULATION
    repressed by EZH2
    Other tyrosine phosphorylation of RUNX3 by activated SRC is associated with the cytoplasmic localization of RUNX3 in gastric and breast cancers
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       loss of function
    in gastric cancers advanced stage by deletion or hypermethylation of the promoter or by protein mislocalization and in bile duct and pancreatic carcinoma
    tumoral     --over  
    in primary and metastatic pancreatic ductal adenocarcinoma
    tumoral     --low  
    by promoter hypermethylation of the CpG island in colorectal cancer
    tumoral   deletion    
    in hepatocellular carcinoma
    tumoral       loss of function
    by hypermethylation in hepatocellular carcinoma
    tumoral       loss of function
    inactivated by aberrant DNA methylation in 73p 100 of primary bladder tumor specimens and 86 p100 (six of seven) of bladder tumor cell lines
    tumoral     --over  
    in basal cell carcinomas
    tumoral     --low  
    in response to hypoxia suppressing RUNX3 (through histone methylation and deacetylation through G9a HMT and HDAC1) in gastric cancer cells at the transcriptional level
    tumoral     --low  
    epigenetic silencing of RUNX3 gene expression by promoter hypermethylation may play an important role in esophageal squamous cell carcinoma development
    tumoral     --over  
    promoted cell growth and inhibited apoptosis in head and neck cancer cells (
    tumoral       loss of function
    loss of RUNX3 expression can enhance the AKT1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer (
    constitutional     --other  
    aberrant expression of RUNX3 was associated with the pathogenesis of Immune thrombocytopenia (ITP)
    Susceptibility
    Variant & Polymorphism
    Candidate gene promoter methylation and silencing of RUNX3 could be useful prognostic markers for both bladder tumor recurrence and progression
    Marker
  • RUNX3 and CAMK2N1 hypermethylation are prognostic marker for epithelial ovarian cancer
    • Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivestomach
    therapeutic approaches including anti-inflammatory regimens that could diminish the hypoxic insult in gastric epithelial cells should, therefore, be considered and adopted to prevent gastric carcinogenesis and progression
    ANIMAL & CELL MODELS
  • Runx3 +/- mice develop lung adenomas spontaneously, providing an animal model for lung tumorigenesis that recapitulate the preneoplastic stage of human lung adenocarcinoma development
  • Runx3-deficient mice develop severe congenital osteopenia