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

Stable Identifier
R-HSA-8877922
Type
Reaction [BlackBoxEvent]
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
16099986 TAZ, a transcriptional modulator of mesenchymal stem cell differentiation

Hopkins, N, McManus, MT, Spiegelman, BM, Hwang, ES, Tian, Y, Sharp, PA, Benjamin, T, Amsterdam, A, Hong, JH, Kalmukova, R, Mueller, E, Yaffe, MB

Science 2005
19801668 Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor

Roca, H, Hatch, NE, Franceschi, RT, Yang, Q, Xiao, G, Ge, C, Jiang, D

J. Biol. Chem. 2009
7891679 Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene

Karsenty, G, Ducy, P

Mol. Cell. Biol. 1995
21173110 Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity

Baron, R, Neff, L, Duda, G, Hesse, E, Kiviranta, R, Toben, D, Atfi, A, Saito, H, Geoffroy, V, Horne, WC, Correa, D, Yamana, K

J. Cell Biol. 2010
11545733 The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation

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

Mol. Cell 2001
14765127 Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription

van Wijnen, AJ, Ito, Y, Medina, R, Lian, JB, Stein, JL, Stein, GS, Sullivan, AJ, Zaidi, SK

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

Coetzee, GA, Baniwal, SK, Khalid, O, Frenkel, B, Buchanan, G, Sir, D

Mol. Endocrinol. 2009
9182762 Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation

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

Cell 1997
12231506 Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms

Ito, Y, Shigesada, K, Wee, HJ, Huang, G

EMBO Rep. 2002
26967290 Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication

Olson, EN, Karsenty, G

Cell 2016
20877012 Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation

Takeda, S, Hamada, M, Yamaguchi, A, Kimura, A, Takayanagi, H, Nakashima, T, Takahashi, S, Isogai, M, Nishikawa, K, Owen, MJ, Kodama, T

J. Clin. Invest. 2010
Participants
Input
Output
Participates
as an event of
This event is regulated
Negatively by
Regulator
RUNX2:ZNF521:HDAC3 [nucleoplasm] (Homo sapiens)
Active Unit
HDAC3 [nucleoplasm]
ZNF521 [nucleoplasm]
Regulator
RUNX2:CBFB:p-Y-YAP1:BGLAP gene [nucleoplasm] (Homo sapiens)
Active Unit
p-Y-YAP1 [nucleoplasm]
Positively by
Regulator
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB):BGLAP gene [nucleoplasm] (Homo sapiens)
Active Unit
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB) [nucleoplasm]
Regulator
RUNX2:MAF:BGLAP gene [nucleoplasm] (Homo sapiens)
Active Unit
RUNX2:MAF [nucleoplasm]
Regulator
RUNX2:RB1:BGLAP gene [nucleoplasm] (Homo sapiens)
Active Unit
RUNX2:RB1 [nucleoplasm]
Regulator
RUNX2:WWTR1:BGLAP gene [nucleoplasm] (Homo sapiens)
Active Unit
RUNX2:WWTR1(TAZ) [nucleoplasm]
Inferred From
Bglap gene expression is negatively regulated by Znf521 (Mus musculus)
Bglap gene expression is negatively regulated by Yap1 (Rattus norvegicus)
Bglap gene expression is stimulated by the complex of Runx2 and Maf, or the complex of Runx2 and Wwtr1 (Taz) (Mus musculus)
Authored
Orlic-Milacic, M  (2016-06-28)
Reviewed
Ducy, P  (2017-08-04)
Created
Orlic-Milacic, M  (2016-06-28)
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