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FLASH GENE

Symbol

RUNX3

contributors: mct - updated : 24-03-2017

HGNC name	runt-related transcription factor 3
HGNC id	10473

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive stomach       highly Lymphoid/Immune lymph node       highly   spleen       highly   tonsils       highly Nervous spinal cord sensory ganglia dorsal root     Homo sapiens Reproductive male system prostate       Respiratory lung

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow

cells

System Cell Pubmed Species Stage Rna symbol Endocrine islet cell (alpha,beta...) Lymphoid/Immune natural killer Homo sapiens Lymphoid/Immune T cell Homo sapiens Nervous neuron Homo sapiens Skeleton osteoblast Homo sapiens Fetal

cell lineage	various lymphoid and myeloid cells
cell lines
fluid/secretion	lymph

at STAGE

Text	expression remains high during later stages of embryonic development when the levels of osteocalcin are maximal

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed cancer digestive stomach 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