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FLASH GENE
Symbol RUNX2 contributors: mct - updated : 16-08-2015
HGNC name runt-related transcription factor 2
HGNC id 10472
Corresponding disease
CCD cleidocranial dysplasia
DUP6PM chromosome 6p21p22 duplication, medial
MDMHB metaphyseal dysplasia with maxillary hypoplasia and brachydactyly
Location 6p21.1      Physical location : 45.296.053 - 45.518.818
Synonym name
  • osteoblast-specific transcription factor 2
  • core binding factor, alpha 1 polypeptide, polyoma enhancer binding protein 2 alpha A
  • acute myeloid leukemia 3 protein
  • oncogene AML-3
  • polyomavirus enhancer-binding protein 2 alpha A subunit
  • SL3/AKV core-binding factor alpha A subunit
  • Synonym symbol(s) PEPB2AA, OSF2, CBFA1, PEBP2A1, CCD1, RUN2, AML3, PEBP2aA1, MGC120023, MGC120022
    DNA
    TYPE functioning gene
    STRUCTURE 222.77 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   enhancer
    text structure an osteoblast-specific enhancer in the promoter whose activity is achieved by the combination of an inhibitory and an activatory mechanism (six copies of the osteoblastic cis-acting element (OSE2) in the proximal promoter region)
    MAPPING cloned Y linked N status confirmed
    Physical map
    CAPN11 6p12 calpain 11 LOC389393 6 LOC389393 SLC29A1 6p21.2-p21.1 solute carrier family 29 (nucleoside transporters), member 1 HSPCB 6p12 heat shock 90kDa protein 1, beta SLC35B2 6p12.1-p11.2 solute carrier family 35, member B2 NFKBIE 6p21.1 nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon LOC391922 6 similar to hypothetical protein MGC33486 MGC33600 6p21.1 hypothetical protein MGC33600 AARSL 6p21.1 alanyl-tRNA synthetase like SPATS1 6p21.1 spermatogenesis associated, serine-rich 1 CDC5L 6p21 CDC5 cell division cycle 5-like (S. pombe) SUPT3H 6p21.3-p21.1 suppressor of Ty 3 homolog (S. cerevisiae) RUNX2 6p21 runt-related transcription factor 2 CLIC5 6p12.1-21.1 chloride intracellular channel 5 ENPP4 6p21.1-p11.2 ectonucleotide pyrophosphatase/phosphodiesterase 4 (putative function) ENPP5 6p21.1-p11.2 ectonucleotide pyrophosphatase/phosphodiesterase 5 (putative function) ACTGP9 6p21.1 actin, gamma pseudogene 9 DSCR1L1 6p21-p11 Down syndrome critical region gene 1-like 1 LOC340211 6p21.1 similar to LINE-1 REVERSE TRANSCRIPTASE HOMOLOG CYP39A1 6p21.1-p11.2 cytochrome P450, family 39, subfamily A, polypeptide 1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 splicing 5487 - 499 - 2006 17000892
    also called OSF2/CBF1b, isoform b
    9 splicing 5553 - 521 - 2006 17000892
    also called OSF2/CBFA1a, isoform a
    7 splicing 5720 - 507 - 2006 17000892
    isoform c
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Endocrinethyroid     Mus musculus
    Hearing/Equilibriumearinnercochlea highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte
    Skeletonosteoblast
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    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
  • 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
  • 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
  • MACF1 promotes osteoblast differentiation by promoting CTNNB1/HNF1A/RUNX2 signaling axis
  • 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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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
    SystemTypeDisorderPubmed
    cancer  
    for therapeutic approaches that disable cancer cell activity
    cancermetastases 
    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