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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
    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
    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
    Type restricted
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Endocrinethyroid     Mus musculus
    Hearing/Equilibriumearinnercochlea highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    cell lineage
    cell lines
    at STAGE
  • 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
    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
  • RUNX family of transcription factor
  • CATEGORY transcription factor , tumor suppressor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    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
  • BMP2-RUNX2-ATF6 signal pathway positively regulates osteoblast differentiation and extracellular matrix mineralization
  • a component
  • heterodimer of and alpha and a beta subunit (CBFB)
  • 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
  • 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
    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
  • 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
    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
    Therapy target
    for therapeutic approaches that disable cancer cell activity
    interaction between RUNX2 and TSSC1 might represent a viable target for therapeutic intervention to inhibit bone metastasis
  • 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