Core-binding factor β interacts with Runx2 and is required for skeletal development

Yoshida, Chisato; Furuichi, Tatsuya; Fujita, Takashi; Fukuyama, Ryo; Kanatani, Naoko; Kobayashi, Shinji; Satake, Masanobu; Takada, Kenji; Komori, Toshihisa

doi:10.1038/ng1015

Cited by 265 publications

(227 citation statements)

References 31 publications

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Section: Introductionmentioning

confidence: 99%

“…Some mutations of Cbfa1 abolish its DNA binding activity (Lee et al, 1997;Zhou et al, 1999) and others disturb the association of Cbfa1 to its binding partners, including Smads (Xie et al, 2000). It was found that several Cbfa1-binding proteins such as retinoblastoma protein (pRb) (Thomas et al, 2001), p204 (Liu et al, 2005), and Core binding factor ␤ ( Kundu et al, 2002;Yoshida et al, 2002) may also play critical roles in bone development.Inhibitor of differentiation (Id) proteins belong to the helix-loop-helix (HLH) family. Id proteins function as global regulators of gene expression during cell growth and differentiation (reviewed in Ruzinova and Benezra, 2003;Wong et al, 2004).…”

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confidence: 99%

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p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

Luan

Yang

et al. 2008

MBoC

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Id proteins play important roles in osteogenic differentiation; however, the molecular mechanism remains unknown. In this study, we established that inhibitor of differentiation (Id) proteins, including Id1, Id2, and Id3, associate with core binding factor ␣-1 (Cbfa1) to cause diminished transcription of the alkaline phosphatase (ALP) and osteocalcin (OCL) gene, leading to less ALP activity and osteocalcin (OCL) production. Id acts by inhibiting the sequence-specific binding of Cbfa1 to DNA and by decreasing the expression of Cbfa1 in cells undergoing osteogenic differentiation. p204, an interferon-inducible protein that interacts with both Cbfa1 and Id2, overcame the Id2-mediated inhibition of Cbfa1-induced ALP activity and OCL production. We show that 1) p204 disturbed the binding of Id2 to Cbfa1 and enabled Cbfa1 to bind to the promoters of its target genes and 2) that p204 promoted the translocation from nucleus to the cytoplasm and accelerated the degradation of Id2 by ubiquitin-proteasome pathway during osteogenesis. Nucleus export signal (NES) of p204 is required for the p204-enhanced cytoplasmic translocation and degradation of Id2, because a p204 mutant lacking NES lost these activities. Together, Cbfa1, p204, and Id proteins form a regulatory circuit and act in concert to regulate osteoblast differentiation. INTRODUCTIONThe differentiation of uncommitted mesenchymal cells to osteoblasts is a fundamental process in embryonic development and bone repair. The bone morphogenetic proteins (BMPs) are important regulators of this process (Heldin et al., 1997;Miyazono et al., 2000). They function by binding cell surface receptors; signaling by Smad proteins; and activating bone-specific genes, including core binding factor ␣-1 (Cbfa1) (Ducy, 2000;Miyazono et al., 2001;Attisano and Wrana, 2002). This process is positively or negatively regulated by a variety of coactivators and corepressors (Ducy et al., 2000;Miyazono et al., 2001;Attisano and Wrana, 2002). Cbfa1, also known as Runx2, PeBP2␣A, Osf2, or AML3, is a member of the runt family of transcription factors. It is an essential transcription factor of osteoblast and bone formation (Ducy, 2000). During skeletal development, Cbfa1 is observed first in early mesenchymal condensations, and it is then principally expressed in osteoblasts . Cbfa1 Ϫ/Ϫ mice exhibit a complete lack of ossification, and they die immediately after birth (Komori et al., 1997). Cbfa1 maintains osteoblastic function by regulating the expression of several bone-specific genes such as osteopontin and osteocalcin and by controlling bone extracellular matrix deposition (Ducy, 2000). Mutations in Cbfa1 are found in 65-80% of individuals with cleidocranial dysplasia (CCD) (Lee et al., 1997;Mundlos and Olsen, 1997;Zhou et al., 1999). The molecular mechanisms underlying the pathogenesis of CCD are not completely defined. Some mutations of Cbfa1 abolish its DNA binding activity (Lee et al., 1997;Zhou et al., 1999) and others disturb the association of Cbfa1 to its binding partners, including Sma...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

Luan

Yang

et al. 2008

MBoC

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“…Osteoblast differentiation and maturation are crucial events in the formation of new bone and determination of bone quality (Nakashima et al, 2002;Yoshida et al, 2002;Komori, 2010). Bone formation begins with the differentiation of osteoblasts from pluripotent mesenchymal cells.…”

Section: Introductionmentioning

confidence: 99%

“…

IntroductionOsteoblast differentiation and maturation are crucial events in the formation of new bone and determination of bone quality (Nakashima et al, 2002;Yoshida et al, 2002;Komori, 2010). Bone formation begins with the differentiation of osteoblasts from pluripotent mesenchymal cells.

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confidence: 99%

Type XII collagen regulates osteoblast polarity and communication during bone formation

Izu¹,

Sun²,

Zwolanek³

et al. 2011

J Exp Med

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Abbreviations used in this paper: CT, computed tomography; FACIT, fibrilassociated collagen with interrupted triple helices; HA, hydroxyapatite; H&E, hematoxylin and eosin; HU, Hounsfield unit; shRNA, short hairpin RNA; TMDn, tissue mineral density; TRAP, tartrate resistance acid phosphatase. IntroductionOsteoblast differentiation and maturation are crucial events in the formation of new bone and determination of bone quality (Nakashima et al., 2002;Yoshida et al., 2002;Komori, 2010). Bone formation begins with the differentiation of osteoblasts from pluripotent mesenchymal cells. The progenitors migrate to the sites of bone matrix deposition and differentiate into fully functional, bone matrix-producing osteoblasts (Imai et al., 1998). These events are regulated by the expression of runtrelated gene 2 (Runx2, also known as Cbfa1) and sp7 transcription factor (Sp7, also known as osterix) and by canonical Wnt signaling followed by the secretion of specific bone matrix proteins such as type I collagen (Col1a1), secreted phosphoprotein1 (Spp1, also known as osteopontin), integrin-binding sialoprotein (Ibsp), and bone -carboxyglutamate protein (Bglap, also known as osteocalcin; Harada and Rodan, 2003;Koga et al., 2005). In addition to these changes in gene expression and matrix protein secretion, the mature osteoblasts become aligned along regions of bone deposition with an epithelioid arrangement. The mature, terminally differentiated osteoblasts are highly polarized relative to the site of bone matrix deposition (Ilvesaro et al., 1999;Nakashima et al., 2002;Stains et al., 2002). These features are common to periosteal and endosteal bone and both long and flat bones. Therefore, the alignment, polarization, and interaction of osteoblasts are important events necessary for production of a functional bone matrix.Cell motility, communication, and shape are controlled via the local microenvironment where the extracellular matrix provides a substrate for cell anchorage, stores and presents growth factors or cytokines, and serves as a tissue scaffold (Rozario and DeSimone, 2010). The extracellular matrix interacts with the intracellular actin cytoskeleton via transmembrane proteins that affect cytoskeletal organization, cell motility and polarity, proliferation, and survival (Berthiaume et al., 1996;Geiger et al., 2001;Théry et al., 2005;Parsons et al., 2010;Kim et al., 2011). Thus, extracellular matrix-transmembrane protein-cytoskeleton D ifferentiated osteoblasts are polarized in regions of bone deposition, demonstrate extensive cell interaction and communication, and are responsible for bone formation and quality. Type XII collagen is a fibril-associated collagen with interrupted triple helices and has been implicated in the osteoblast response to mechanical forces. Type XII collagen is expressed by osteoblasts and localizes to areas of bone formation. A transgenic mouse null for type XII collagen exhibits skeletal abnormalities including shorter, more slender long bones with decreased mechanical strength as well as a...

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“…The free RHD exists in a conformation in which affinity for DNA is nonoptimal, and CBF␤ binding to the RHD triggers a switch in the RHD structure that stabilizes it in a conformation for sustained DNA binding (13). CBF␤ is essential for Runx protein function because a homozygous mutation of CBF␤ results in a complete lack of fetal liver hematopoiesis (1,2) and severely defective bone formation (14,15).…”

mentioning

confidence: 99%

AML1/Runx1 Recruits Calcineurin to Regulate Granulocyte Macrophage Colony-stimulating Factor by Ets1 Activation

Liu

Holm

Xie

et al. 2004

Journal of Biological Chemistry

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Acute myeloid leukemia 1 (AML1), also denoted Runx1, is a transcription factor essential for hematopoiesis, and the AML1 gene is the most common target of chromosomal translocations in human leukemias. AML1 binds to sequences present in the regulatory regions of a number of hematopoiesis-specific genes, including certain cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) up-regulated after T cell receptor stimulation. Here we show that both subunits of the Ca 2؉ / calmodulin-dependent protein phosphatase calcineurin (CN), which is activated upon T cell receptor stimulation, interact directly with the N-terminal runt homology domain-containing part of AML1. The regulatory CN subunit binds AML1 with a higher affinity and in addition also interacts with the isolated runt homology domain. The related Runx2 transcription factor, which is essential for bone formation, also interacts with CN. A constitutively active derivative of CN is shown to activate synergistically the GM-CSF promoter/enhancer together with AML1 or Runx2. We also provide evidence that relief of the negative effect of the AML1 sites is important for Ca 2؉ activation of the GM-CSF promoter/enhancer and that AML1 overexpression increases this Ca 2؉ activation. Both subunits of CN interact with AML1 in coimmunoprecipitation analyses, and confocal microscopy analysis of cells expressing fluorescence-tagged protein derivatives shows that CN can be recruited to the nucleus by AML1 in vivo. Mutant analysis of the GM-CSF promoter shows that the Ets1 binding site of the promoter is essential for the synergy between AML1 and CN in Jurkat T cells. Analysis of the effects of inhibitors of the protein kinase glycogen synthase kinase-3␤ and in vitro phosphorylation/dephosphorylation analysis of Ets1 suggest that glycogen synthase kinase-3␤-phosphorylated Ets1 is a target of AML1-recruited CN phosphatase at the GM-CSF promoter.

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Core-binding factor β interacts with Runx2 and is required for skeletal development

Cited by 265 publications

References 31 publications

p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

Type XII collagen regulates osteoblast polarity and communication during bone formation

AML1/Runx1 Recruits Calcineurin to Regulate Granulocyte Macrophage Colony-stimulating Factor by Ets1 Activation

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