Reactome | BGLAP gene expression is stimulated by RUNX2, WWTR1 and RB1 and inhibited by AR, YAP1 and ZNF521

BGLAP gene expression is stimulated by RUNX2, WWTR1 and RB1 and inhibited by AR, YAP1 and ZNF521

Stable Identifier

R-HSA-8877922

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

nucleoplasm, endoplasmic reticulum lumen

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BGLAP gene expression is stimulated by RUNX2, WWTR1 and RB1 and inhibited by AR, YAP1 and ZNF521

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Binding of RUNX2 to the OSE2 element in the promoter of the BGLAP (osteocalcin, OC) gene stimulates BGLAP transcription (Ducy and Karsenty 1995, Ducy et al. 1997). When RUNX2 binds the OSE2 element in complex with the MAF transcription factor, BGLAP transcription is enhanced (Nishikawa et al. 2010). BGLAP gene transcription is also directly stimulated by the complex of RUNX2 and WWTR1 (TAZ) (Hong et al. 2005), as well as the complex of RUNX2 and RB1 (Thomas et al. 2001). Phosphorylation of RUNX2, in the context of the RUNX2:CBFB complex, increases its association with the BGLAP promoter and enhances BGLAP transcription (Wee et al. 2002, Ge et al. 2009). Osteocalcin, a bone-derived hormone, is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016).
Association of the activated androgen receptor (AR) with RUNX2 prevents binding of RUNX2 to the BGLAP promoter (Baniwal et al. 2009). Based on studies in rat, when YAP1, phosphorylated on an unknown tyrosine residue by SRC and/or YES1, is present in the complex with RUNX2 at the BGLAP gene promoter, transcription of the BGLAP gene is inhibited (Zaidi et al. 2004). Signaling by SRC is known to inhibit osteoblast differentiation (Marzia et al. 2000). Based on studies in mice, binding to ZNF521 (ZNP521) inhibits RUNX2-mediated activation of target promoters, such as BGLAP. HDAC3 is needed for ZNF521 to inhibit RUNX2-mediated transcription from the BGLAP promoter. Action of ZNF521 antagonizes RUNX2 during mesenchymal commitment to the osteoblast lineage and during osteoblast maturation (Hesse et al. 2010).

Literature References

PubMed ID	Title	Journal	Year
19801668	Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor Ge, C, Xiao, G, Jiang, D, Yang, Q, Hatch, NE, Roca, H, Franceschi, RT	J. Biol. Chem.	2009
16099986	TAZ, a transcriptional modulator of mesenchymal stem cell differentiation Hong, JH, Hwang, ES, McManus, MT, Amsterdam, A, Tian, Y, Kalmukova, R, Mueller, E, Benjamin, T, Spiegelman, BM, Sharp, PA, Hopkins, N, Yaffe, MB	Science	2005
7891679	Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene Ducy, P, Karsenty, G	Mol. Cell. Biol.	1995
21173110	Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity Hesse, E, Saito, H, Kiviranta, R, Correa, D, Yamana, K, Neff, L, Toben, D, Duda, G, Atfi, A, Geoffroy, V, Horne, WC, Baron, R	J. Cell Biol.	2010
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
14765127	Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription Zaidi, SK, Sullivan, AJ, Medina, R, Ito, Y, van Wijnen, AJ, Stein, JL, Lian, JB, Stein, GS	EMBO J.	2004
19389811	Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA Baniwal, SK, Khalid, O, Sir, D, Buchanan, G, Coetzee, GA, Frenkel, B	Mol. Endocrinol.	2009
9182762	Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation Ducy, P, Zhang, R, Geoffroy, V, Ridall, AL, Karsenty, G	Cell	1997
12231506	Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms Wee, HJ, Huang, G, Shigesada, K, Ito, Y	EMBO Rep.	2002
26967290	Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication Karsenty, G, Olson, EN	Cell	2016
20877012	Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation Nishikawa, K, Nakashima, T, Takeda, S, Isogai, M, Hamada, M, Kimura, A, Kodama, T, Yamaguchi, A, Owen, MJ, Takahashi, S, Takayanagi, H	J. Clin. Invest.	2010