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FLASH GENE

Symbol

RUNX2

contributors: mct - updated : 16-08-2020

HGNC name	runt-related transcription factor 2
HGNC id	10472

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal alanine and glutamine stretches (Q/A), sequence unique to RUNX2 contributing to a competent structure of RUNX2 that is required for nuclear localization, DNA binding, and transactivation function
	a putative ATP binding site Runt domain forming a DNA-binding motif with an Ig-like protein fold, related to the DNA-binding domain of TP53
	a nuclear matrix targeting signal
	a proline/serine/threonine (PST)
	C terminal transactivation domain

conjugated

PhosphoP

mono polymer

heteromer , monomer , dimer

HOMOLOGY

interspecies	homolog to Drosophila Runt pair rule-related transcription factor
	homolog to rattus Runx2 (98,3 pc)
	homolog to murine Runx2 (98,1 pc)

intraspecies

homolog to AML1 related gene AML3,homologous to mouse PEBP2 alpha

Homologene

FAMILY

RUNX family of transcription factor

CATEGORY

transcription factor , tumor suppressor , protooncogene

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	regulating osteoblast differentiation, essential for membranous and endochondral bone formation
	involved in hematopoietic stem cells differentiation
	playing important roles in multiple steps of skeletal development and crucial roles in chondrocyte maturation and in the specification of cartilage phenotypes
	required through its intranuclear trafficking in breast cancer cell to form osteolytic lesions in bone
	required for osteoblast recruitment and differentiation from mesenchymal stem cells
	play a critical role on increasing TGFBR1 expression by osteoblasts
	functioning in cooperation with DLX5 or a related factor to activate osteoblast-specific gene expression
	enhances perichondrial expression of FGF18, a regulator of chondrocyte maturation
	inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium
	may sensitize cAMP-related G protein-coupled receptor signaling by activating GPER and repressing RGS2 gene expression in osteoblasts to increase responsiveness to mitogenic signals
	may regulate G protein-signaling pathways to modify how osteoblasts respond to mitogenic stimuli
	playing a role in promoting chondrocyte maturation and hypertrophy at least in part, via the stimulation of NFATC2 expression
	potential role of the STAT5B-RUNX interaction in lymphocyte development
	in actively proliferating cells, regulates the expression of specific target genes as cells enter and exit mitosis
	plays a critical role in parathyroid hormone (PTH)-induced bone resorption
	differential biological functions of RUNX2, SP7, and DSPP during odontogenesis and osteogenesis
	acting as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression
	may function as a tumor suppressor in some cell types and have oncogenic potential in others
	inhibits MYST4-dependent transcriptional activation
	interaction with SATB2 results in enhanced DNA binding and transcativation by these transcription factors
	plays a pivotal role in osteogenic conversion tightly coupled with repression of the smooth muscle cells phenotype in atherosclerotic lesions
	functioning with TLE1 in epigenetic repression of ribosomal RNA genes
	with RUNX2, and UBTF together occupy nucleolar organizing regions (NORs) during mitosis and control histone modifications.
	regulates survivin expression in malignant epithelial cells and is a critical factor in BMP signaling that protects cancer cells against apoptosis
	during dentinogenesis, RUNX2 is down-regulated, RUNX2 inhibits the terminal differentiation of odontoblasts
	regulates the expression of ODAM and nuclear ODAM serves an important regulatory function in the mineralization of enamel through the regulation of MMP20 apart from a different, currently unidentified, function of extracellular ODAM)
	plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis
	essential transcription factor that controls bone and tooth development by regulating osteoblast and odontoblast differentiation
	inhibits chondrocyte differentiation at an early stage, and its expression at appropriate level, times and spaces during embryogenesis is essential for skeletal development
	attenuates growth and stimulates maturation of osteoblasts during bone formation but is also robustly expressed in a subset of osteosarcomas, as well as in metastatic breast and prostate tumors
	RUNX2, HIF1A, and VEGFA may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation
	RUNX2 and AXIN2 regulate craniofacial development and skeletal maintenance
	a RUNX2-AXIN2 regulatory mechanism controls the pace of calvarial bone formation
	ALCAM expression on osteoblast is directly correlated with RUNX2 expression and high hematopoiesis enhancing activity (HEA)
	master transcriptional factor for osteoblast differentiation
	both RUNX2 and RUNX3 mRNAs were differentially up regulated during fracture healing
	mediates breast cancer-induced osteolytic bone disease by transcriptional regulation of TSSC1 expression
	SOX6 and RUNX2 play essential roles in the communication of chondroption factor that is crucial for the communication of chondrocyte and osteoblast
	novel function of SOX6 and RUNX2 in the endochondral ossification
	plays a major role in chondrocyte maturation, and regulates chondrocyte proliferation by directly regulating IHH expression
	is essential for osteoblast differentiation and is required for the proliferation of osteoprogenitors
	involved in regulation of osteoblast differentiation with SP7 and other factors such as ATF4

CELLULAR PROCESS	nucleotide, transcription, regulation
	cell organization/biogenesis

PHYSIOLOGICAL PROCESS

development , ossification

text	essential for osteoblast differentiation and bone development; regulatory for chondrocyte maturation factor; skeletal morphogenesis

PATHWAY

metabolism

signaling

	BMP2-RUNX2-ATF6 signal pathway positively regulates osteoblast differentiation and extracellular matrix mineralization
	RUNX2-NFIC-SP7 pathway is one of the key factors that regulate ameloblast differentiation

a component

heterodimer of and alpha and a beta subunit (CBFB)

INTERACTION

DNA	binding to the osteocalcin promoter
	binding DNA as a monomer or as a subunit of heterodimeric complex
	binding to the core site of a number of enhancers and promoters (including murine leukemia virus, polyomavirus enhancer, T-cells receptors enhancers, osteopontin, bone sialoprotein, alpha1(I)collagen, LCK, IL3 and GM-CSF promoters)

RNA

small molecule

protein	interacting with SMAD (MADHs) genes, signal transducers of the TGFBR-BMP pathway
	controlling SPP1
	target of TWIST in osteoblasts
	binding to an osteoblast-specific cis-acting element, termed OSE2, in the promoter of osteocalcin
	interacting with HDAC4 (taget for repression by HDAC4 in the developing skeleton)
	binding to the proximal SOST promoter contributing to differential SOST expression in two osteosarcoma cell lines
	cooperatively interact with BMP2 to stimulate osteoblast gene expression
	interacting with TRAM2 (may regulate TRAM2 expression in a BMP-dependent manner, and TRAM2 may participate in the overall osteogenic function of RUNX2)
	interacting with STAT5B (inhibits the nuclear localization of RUNX proteins and retains them in the cytoplasm)
	associations with co-repressors including histone deacetylase 7 (HDAC7) (BMP signaling regulates RUNX2 activity via PKD-dependent inhibition of HDAC7 transcriptional repression)
	interacting with HIVEP, G22P1, XRCC5, MYST3, MYST4
	interacting with ARID4A (regulating RUNX2 expression, regulation mediated through the proximal P2 RUNX2 promoter)
	RUNX2 and FOXO1 interact with each other and cooperate in the transcriptional regulation of osteoblast markers
	interacting with ZNF521 (the balance and molecular interplay between ZNF521 and RUNX2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis)
	RUNX2, a pro-metastatic transcription factor, functionally interacts with the Androgen Receptor (AR) to regulate PIP expression
	HMGB2 regulates MSC (mesenchymal stem cell) chondrogenesis in part by modulating the LEF1-dependent transactivation of RUNX2
	in coronary artery smooth muscle cell, BMP2 increases oxidant stress and ER stress to increase RUNX2 expression and promote vascular smooth muscle cell calcification
	PANX3 may serve an important role in bone development, and is a novel target for RUNX2-dependent signaling
	is the most potent transcriptional partner of CEBPB in chondrocytes
	is essential to the BMP2 induction of ATF6 expression but is not needed to determine the subcellular localization of ATF6
	targeting RUNX2 in hypertrophic chondrocytes upregulates expression of COL10A1 and other marker genes (such as SOX9)
	HTR2A, HTR2B, HTR2C are implicated as being critical for induction of PTHLH and RUNX2
	NELL1 is an important growth factor for regulation of osteochondral differentiation, by regulating both RUNX2 and SOX9 expression within the calvarium
	EHMT2 functioned as a positive regulator for RUNX2 target genes
	XBP1 associates with RUNX2 and enhances RUNX2-induced chondrocyte hypertrophy
	physical and functional interaction between SP7 and RUNX2 were necessary for the induction of MMP13 during endochondral ossification
	RUNX2, HDAC3, repress AXIN2 transcription in osteoblasts
	RUNX2 binds several regions of the AXIN2 promoter and RUNX2-mediated repression of AXIN2 transcription depends on HDAC3
	CBL interacts with the transcription factor STAT5A, and STAT5A forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis
	KAT2B directly binds to RUNX2 and acetylates RUNX2, leading to an increase in its transcriptional activity
	DCLK1 represses osteoblast activation by antagonizing RUNX2, the master transcription factor in osteoblasts
	RUNX2 induces bone osteolysis by transcriptional suppression of TSSC1
	KDM6B plays important roles in osteoblast differentiation and regulates the expressions of IBSP and BGLAP via transcription factors RUNX2 and SP7
	MAPK7/MAP2K5 pathway mediates fluid shear stress induced RUNX2 expression in osteoblast differentiation
	GATA4 interacted with DLX5 and subsequently decreased DLX5 binding activity to RUNX2 promoter region
	RUNX2 stabilizes NAA10 in osteoblasts during BMP2-induced differentiation, and NAA10 in turn controls this differentiation by inhibiting RUNX2
	HDAC7 suppresses RUNX2 activity and osteoblast differentiation
	KDM6B associates with RUNX2 to promote proliferation and hypertrophy of chondrocytes
	WNT1 stimulates osteogenic differentiation and mineralization of human periodontal ligament fibroblasts (hPLFs), mainly by activating the canonical WNT/CTNNB1 pathway, in which RUNX2 is a key downstream regulator
	RUNX2 regulates IPO8 gene transcription, and may have a contributory role in osteoblast differentiation
	MACF1 promotes osteoblast differentiation by promoting CTNNB1/HNF1A/RUNX2 signaling axis
	interaction between LEF1 and WWTR1 is crucial for the osteoblastogenic activity of WNT3A and LEF1 and WWTR1 contribute to the cooperative effect of WNT3A and BMP2 on osteoblast differentiation through association with RUNX2
	RUNX2 induces SP7 expression, and RUNX2, SP7, and canonical Wnt signaling are required for the differentiation of preosteoblasts to immature osteoblasts
	RUNX2/CBFB regulates the proliferation and differentiation of chondrocytes and osteoblast-lineage cells by activating multiple signaling pathways and via their reciprocal regulation

cell & other

REGULATION

induced by

SRF (overexpression of SRF induced RUNX2 transactivity in control cells and restored RUNX2 transactivity in the SRF-deficient cells)

repressed by

SNAI2 to control osteoblasts differentiation

Phosphorylated by

ERK/MAPK-mediated phosphorylation of RUNX2 is a critical step in the response of preosteoblasts to dynamic loading and define a novel mechanism to explain how mechanical signals induce gene expression in bone

Other	regulated by vitamin D3, MSX2
	regulated by IGF-1 through sequential activation of the PI3K/Pak1 and ERK1/2 signaling cascade
	transcriptional regulation of the promoter by bone morphogenetic protein-7(BMP7)
	hyper-phosphorylated by CDC2/cyclin B during mitosis, and dynamically converted into a hypo-phosphorylated form by PP1/PP2A-dependent dephosphorylation after mitosis to support the post-mitotic regulation of RUNX2 target genes
	regulation by phosphorylation necessary for PKA stimulated MMP13 promoter activation and this event may be critical for bone remodeling
	ERK MAPK enhances RUNX2 acetylation and stabilization
	regulatrd by ARID4A, a potent coactivator of RUNX2 transcriptional activity
	should be inhibited in odontoblasts to encourage normal cell maturation, differentiation and dentinogenesis
	regulated by EHMT2 , a novel regulator for RUNX2 activity

ASSOCIATED DISORDERS

corresponding disease(s)

CCD , DUP6PM , MDMHB

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in expression of osteogenesis-related transcription factors RUNX2 and Osterix by TGFB3 induction of adipose-derived stromal cells during chondrogenesis tumoral     --over   in chondrosarcoma cells constitutional     --over   may induce transdifferentiation from odontoblasts to osteoblasts tumoral     --over   in breast and prostate cancers predisposed to skeletal metastasis

Susceptibility

to osteoporotic fracture (with decreased BMD)

Variant & Polymorphism	A allele was associated with increased BMD and was protective against a common form of osteoporotic fracture

Candidate gene	abnormally expressed in highly metastatic prostate cancer cells, may be a key regulator of events associated with prostate cancer metastatic bone disease
Marker
Therapy target
	System Type Disorder Pubmed cancer     for therapeutic approaches that disable cancer cell activity cancer metastases   interaction between RUNX2 and TSSC1 might represent a viable target for therapeutic intervention to inhibit bone metastasis

ANIMAL & CELL MODELS

	Mice overexpressing Runx2 in osteoblasts have an abnormally low number of osteocytes in cortical bone
	Runx2-null mice die at birth lacking a mineralized skeleton, and are in a hypothyroid state
	Runx2 haploinsufficient mice mimic features of human cleidocranial dysplasia in that they present with hypoplastic clavicles and delayed cranial suture development with persistent fontanels in the calvaria