Transcriptional regulation by RUNX2

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R-HSA-8878166
Type
Pathway
Species
Homo sapiens
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RUNX2 (CBFA1 or AML3) transcription factor, similar to other RUNX family members, RUNX1 and RUNX3, can function in complex with CBFB (CBF-beta) (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002). RUNX2 mainly regulates transcription of genes involved in skeletal development (reviewed in Karsenty 2008). RUNX2 is involved in development of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. RUNX2 stimulates transcription of the BGLAP gene (Ducy and Karsenty 1995, Ducy et al. 1997), which encodes Osteocalcin, a bone-derived hormone which is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). RUNX2 directly controls the expression of most genes associated with osteoblast differentiation and function (Sato et al. 1998, Ducy et al. 1999, Roce et al. 2005). RUNX2-mediated transcriptional regulation of several genes involved in GPCR (G protein coupled receptor) signaling is implicated in the control of growth of osteoblast progenitors (Teplyuk et al. 2009). RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004). Germline loss-of-function mutations of the RUNX2 gene are associated with cleidocranial dysplasia syndrome (CCD), an autosomal skeletal disorder (reviewed in Jaruga et al. 2016). The function of RUNX2 is frequently disrupted in osteosarcoma (reviewed in Mortus et al. 2014). Vitamin D3 is implicated in regulation of transcriptional activity of the RUNX2:CBFB complex (Underwood et al. 2012).

RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA) (Kammerer et al. 2013), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1) (Zhang et al. 2012), NKX3-2 (BAPX1) (Tribioli and Lufkin 1999, Lengner et al. 2005), DLX5 (Robledo et al. 2002, Lee et al. 2005) and MSX2 (Lee et al. 2005). RUNX2 can autoregulate, by directly inhibiting its own transcription (Drissi et al. 2000). Several E3 ubiquitin ligases target RUNX2 for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016). Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 (Bialek et al. 2004) and RB1 (Thomas et al. 2001).

RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 (Li et al. 2016) and the ITGBL1 gene, encoding Integrin beta like protein 1 (Li et al. 2015). RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 (Pande et al. 2013). RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells (Tandon et al. 2014).

RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).

For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015.

Literature References
PubMed ID Title Journal Year
11545733 The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation

Thomas, DM, Carty, SA, Piscopo, DM, Lee, JS, Wang, WF, Forrester, WC, Hinds, PW

Mol. Cell 2001
22189971 Regulation of RUNX2 transcription factor-DNA interactions and cell proliferation by vitamin D3 (cholecalciferol) prohormone activity

Underwood, KF, D'Souza, DR, Mochin-Peters, M, Pierce, AD, Kommineni, S, Choe, M, Bennett, J, Gnatt, A, Habtemariam, B, MacKerell, AD, Passaniti, A

J. Bone Miner. Res. 2012
15030764 A twist code determines the onset of osteoblast differentiation

Bialek, P, Kern, B, Yang, X, Schrock, M, Sosic, D, Hong, N, Wu, H, Yu, K, Ornitz, DM, Olson, EN, Justice, MJ, Karsenty, G

Dev. Cell 2004
10572046 The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen

Tribioli, C, Lufkin, T

Development 1999
11857736 Mutations in the RUNX2 gene in patients with cleidocranial dysplasia

Otto, F, Kanegane, H, Mundlos, S

Hum. Mutat. 2002
15107406 Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog

Yoshida, CA, Yamamoto, H, Fujita, T, Furuichi, T, Ito, K, Inoue, K, Yamana, K, Zanma, A, Takada, K, Ito, Y, Komori, T

Genes Dev. 2004
12434156 Cbfbeta interacts with Runx2 and has a critical role in bone development

Kundu, M, Javed, A, Jeon, JP, Horner, A, Shum, L, Eckhaus, M, Muenke, M, Lian, JB, Yang, Y, Nuckolls, GH, Stein, GS, Liu, PP

Nat. Genet. 2002
26404249 Role of RUNX2 in Breast Carcinogenesis

Wysokinski, D, Blasiak, J, Pawlowska, E

Int J Mol Sci 2015
26060017 ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway

Li, XQ, Du, X, Li, DM, Kong, PZ, Sun, Y, Liu, PF, Wang, QS, Feng, YM

Cancer Res. 2015
18625716 Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors

Teplyuk, NM, Galindo, M, Teplyuk, VI, Pratap, J, Young, DW, Lapointe, D, Javed, A, Stein, JL, Lian, JB, Stein, GS, van Wijnen, AJ

J. Biol. Chem. 2008
12000792 The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development

Robledo, RF, Rajan, L, Li, X, Lufkin, T

Genes Dev. 2002
7891679 Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene

Ducy, P, Karsenty, G

Mol. Cell. Biol. 1995
19020999 RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors

Zhang, HY, Jin, L, Stilling, GA, Ruebel, KH, Coonse, K, Tanizaki, Y, Raz, A, Lloyd, RV

Endocrine 2009
23403054 Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα) are both transcriptional regulators of the Runx2-I isoform

Kammerer, M, Gutzwiller, S, Stauffer, D, Delhon, I, Seltenmeyer, Y, Fournier, B

Mol. Cell. Endocrinol. 2013
15703179 Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation

Lengner, CJ, Hassan, MQ, Serra, RW, Lepper, C, van Wijnen, AJ, Stein, JL, Lian, JB, Stein, GS

J. Biol. Chem. 2005
24924170 Developmental pathways hijacked by osteosarcoma

Mortus, JR, Zhang, Y, Hughes, DP

Adv. Exp. Med. Biol. 2014
23389849 Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells

Pande, S, Browne, G, Padmanabhan, S, Zaidi, SK, Lian, JB, van Wijnen, AJ, Stein, JL, Stein, GS

J. Cell. Physiol. 2013
9182762 Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation

Ducy, P, Zhang, R, Geoffroy, V, Ridall, AL, Karsenty, G

Cell 1997
12434152 Core-binding factor beta interacts with Runx2 and is required for skeletal development

Yoshida, CA, Furuichi, T, Fujita, T, Fukuyama, R, Kanatani, N, Kobayashi, S, Satake, M, Takada, K, Komori, T

Nat. Genet. 2002
17142326 Dominance of SOX9 function over RUNX2 during skeletogenesis

Zhou, G, Zheng, Q, Engin, F, Munivez, E, Chen, Y, Sebald, E, Krakow, D, Lee, B

Proc. Natl. Acad. Sci. U.S.A. 2006
11230154 Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice

Takeda, S, Bonnamy, JP, Owen, MJ, Ducy, P, Karsenty, G

Genes Dev. 2001
27272193 Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation

Jaruga, A, Hordyjewska, E, Kandzierski, G, Tylzanowski, P

Clin. Genet. 2016
22422618 Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis

Zhang, YY, Li, X, Qian, SW, Guo, L, Huang, HY, He, Q, Liu, Y, Ma, CG, Tang, QQ

Mol. Endocrinol. 2012
24479521 Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells

Tandon, M, Chen, Z, Pratap, J

Breast Cancer Res. 2014
16000302 Cooperative interactions between RUNX2 and homeodomain protein-binding sites are critical for the osteoblast-specific expression of the bone sialoprotein gene

Roca, H, Phimphilai, M, Gopalakrishnan, R, Xiao, G, Franceschi, RT

J. Biol. Chem. 2005
18767962 Transcriptional control of skeletogenesis

Karsenty, G

Annu Rev Genomics Hum Genet 2008
25592647 The RUNX family: developmental regulators in cancer

Ito, Y, Bae, SC, Chuang, LS

Nat. Rev. Cancer 2015
10816326 GALECTIN-3 expression in differentiating human myeloid cells

Le Marer, N

Cell Biol. Int. 2000
10215629 A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development

Ducy, P, Starbuck, M, Priemel, M, Shen, J, Pinero, G, Geoffroy, V, Amling, M, Karsenty, G

Genes Dev. 1999
22189423 Building strong bones: molecular regulation of the osteoblast lineage

Long, F

Nat. Rev. Mol. Cell Biol. 2011
10911365 Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene

Drissi, H, Luc, Q, Shakoori, R, Chuva De Sousa Lopes, S, Choi, JY, Terry, A, Hu, M, Jones, S, Neil, JC, Lian, JB, Stein, JL, Van Wijnen, AJ, Stein, GS

J. Cell. Physiol. 2000
19179305 Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice

Kuo, YH, Zaidi, SK, Gornostaeva, S, Komori, T, Stein, GS, Castilla, LH

Blood 2009
27317874 RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization

Li, XQ, Lu, JT, Tan, CC, Wang, QS, Feng, YM

Cancer Lett. 2016
21931630 Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST

Yang, DC, Yang, MH, Tsai, CC, Huang, TF, Chen, YH, Hung, SC

PLoS ONE 2011
26967290 Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication

Karsenty, G, Olson, EN

Cell 2016
21913213 Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype

Pierce, AD, Anglin, IE, Vitolo, MI, Mochin, MT, Underwood, KF, Goldblum, SE, Kommineni, S, Passaniti, A

J. Cell. Biochem. 2012
9794229 Transcriptional regulation of osteopontin gene in vivo by PEBP2alphaA/CBFA1 and ETS1 in the skeletal tissues

Sato, M, Morii, E, Komori, T, Kawahata, H, Sugimoto, M, Terai, K, Shimizu, H, Yasui, T, Ogihara, H, Yasui, N, Ochi, T, Kitamura, Y, Ito, Y, Nomura, S

Oncogene 1998
18438928 Runx2 is expressed in human glioma cells and mediates the expression of galectin-3

Vladimirova, V, Waha, A, Lückerath, K, Pesheva, P, Probstmeier, R

J. Neurosci. Res. 2008
16115867 Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter

Lee, MH, Kim, YJ, Yoon, WJ, Kim, JI, Kim, BG, Hwang, YS, Wozney, JM, Chi, XZ, Bae, SC, Choi, KY, Cho, JY, Choi, JY, Ryoo, HM

J. Biol. Chem. 2005
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