The Retinoblastoma Protein Is an Essential Mediator of Osteogenesis That Links the p204 Protein to the Cbfa1 Transcription Factor Thereby Increasing Its Activity

Luan, Yi; Yu, Xiuping; Xu, Ke; Ding, Bo; Jin, Yu; Huang, Yan; Yang, Ning; Lengyel, Péter; Cesare, Paul E. Di; Liu, Chuanju

doi:10.1074/jbc.m610943200

Cited by 47 publications

(56 citation statements)

References 62 publications

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“…pRb was found to interact with Cbfa1, and it was required for Cbfa1-mediated osteogenesis (Thomas et al, 2001). pRb is also needed for the association of p204 and Cbfa1 and enhancements of osteogenesis by p204 (Luan et al, 2007). Id2 does not disturb the association of p204 and Cbfa1 ( Figure 7B), and same is also true for the association of pRb and Cbfa1 (data not shown), suggesting that p204 and/or pRb bind to Cbfa1 with higher affinity than does Id2.…”

Section: Discussionmentioning

confidence: 72%

“…We previously reported that p204 acted as a transcriptional coactivator of Cbfa1 and therefore enhanced osteoblast differentiation (Liu et al, 2005) and that pRb is an essential linker between p204 and Cbfa1, thereby increasing its activity (Luan et al, 2007) during the differentiation of pluripotent C2C12 to osteoblast induced by BMP-2. In this study, we report that Id proteins directly associate with Cbfa1 and inhibit Cbfa1-mediated osteogenic differentiation and that p204 overcomes these inhibitions by Id proteins, and we focus on the molecular mechanisms underlying these processes.…”

confidence: 99%

“…p204 may also play an important role in lymphocytic differentiation based on the observation that p204 mRNA levels are higher in less mature double-positive (CD4 ϩ CD8 ϩ ) thymocytes than in single-positive (CD4 ϩ or CD8ϩ) thymocytes (Deftos et al, 2000). Notch1, an essential factor for promoting the maturation of T thymocytes, can transcriptionally up-regulate p204 gene expression during the maturation to both CD4 ϩ and CD8 ϩ singlepositive lineages of CD4 ϩ CD8 ϩ double-positive thymocytes (Deftos et al, 2000).We previously reported that p204 acted as a transcriptional coactivator of Cbfa1 and therefore enhanced osteoblast differentiation (Liu et al, 2005) and that pRb is an essential linker between p204 and Cbfa1, thereby increasing its activity (Luan et al, 2007) during the differentiation of pluripotent C2C12 to osteoblast induced by BMP-2. In this study, we report that Id proteins directly associate with Cbfa1 and inhibit Cbfa1-mediated osteogenic differentiation and that p204 overcomes these inhibitions by Id proteins, and we focus on the molecular mechanisms underlying these processes.…”

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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: Discussionmentioning

confidence: 72%

confidence: 99%

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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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“…We previously reported that p204 associates with Cbfa1 and plays an important role in osteoblast differentiation. 12,24,25 Given that Cbfa1 is also required for the hypertrophic chondrocyte differentiation, we sought to determine whether p204 was also involved in the chondrocyte differentiation. We first examined the expression of p204 in growth plate chondrocytes using immunohistochemistry on tibial growth plates of mouse embryos on postcoital day 18.5.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, forced expression of p204 strongly repressed the IL-3-and M-CSF-dependent proliferation, whereas it promoted the M-CSF-induced macrophage differentiation of FD-Fms cells. 23 We previously reported that p204 acted as a transcriptional coactivator of Cbfa1 and therefore enhanced osteoblast differentiation 12 and that pRb is an essential linker between p204 and Cbfa1 thereby increasing its activity; 24 p204, pRb, Cbfa1 and Ids form a protein interaction network and act in concert in regulating the differentiation of pluripotent C2C12 to osteoblasts. 25 In this study, we describe the expression and function of p204 in hypertrophic chondrocyte differentiation as well as the molecular mechanism involved.…”

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Cbfa1-dependent expression of an interferon-inducible p204 protein is required for chondrocyte differentiation

Zhang

Kong

et al. 2008

Cell Death Differ

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We reported earlier that an interferon-inducible p204 protein serves as a cofactor of Cbfa1 and promotes osteogenesis. Here we establish that p204 demonstrates prominent expression in growth plate chondrocytes. It is differentially expressed in the course of bone morphogenetic protein-2-triggered chondrocyte differentiation of pluripotent C3H10T1/2 cells. This expression is probably due to the activation of p204 gene by Cbfa1 and repression by Sox5 transcription factor. Cbfa1 and Sox5 bind to the 5 0 -flanking regulatory region of p204 gene at their consensus binding elements. Overexpression of p204 accelerates chondrocyte hypertrophy, as revealed by enhanced expression of type X Collagen and matrix metalloproteinase-13; however, knockdown of p204 via an siRNA approach abolishes hypertrophic chondrocyte differentiation. p204 acts as a cofactor of Cbfa1 in chondrocyte hypertrophy: (1) overexpression of p204 augments, whereas suppression of p204 decreases, the Cbfa1-dependent transactivation of a Collagen X-specific reporter gene; (2) p204 enhances Cbfa1-mediated chondrocyte hypertrophy; and (3) p204 associates with Cbfa1 in chondrocyte differentiation. In addition, altered expression of p204 in chondrocyte hypertrophy was accompanied by altered levels of Indian hedgehog (IHH) and parathyroid hormone/parathyroid hormone-related peptide receptor-1 (PTHR1). Collectively, p204 is a novel regulator of chondrocyte differentiation by (1) acting as a coactivator of Cbfa1 and (2) affecting IHH/PTPrP signaling.

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STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice

Baum

Sharma

Organ

et al. 2017

Arthritis & Rheumatology

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Objective Cytosolic DNA sensors detect microbial DNA and promote type I interferon and pro-inflammatory cytokine production through the adaptor stimulator of interferon genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. We identified a novel role for STING in bone in arthritic DNase II/IFNaR double deficient (DKO) mice, and sought to define the bone phenotype in these mice and to address mechanism. Methods Bone parameters were evaluated in DKO, STING/DNaseII/IFNaR triple deficient and control mice by microcomputed tomography and histomorphometry. Cell culture techniques were employed to determine parameters of osteoclast and osteoblast differentiation and function. Nanostring and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation. Results Despite the expression of pro-inflammatory cytokines that would be expected to induce bone loss in the skeleton in DKO mice, we demonstrate the paradoxical accumulation of bone in the long bones and spleen, sites of erythropoiesis and robust DNA accrual, as well as the induction of factors promoting osteoblast recruitment and function. STING deficiency significantly inhibits this bone accrual. Conclusions These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. We demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in autoimmune diseases.

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The Retinoblastoma Protein Is an Essential Mediator of Osteogenesis That Links the p204 Protein to the Cbfa1 Transcription Factor Thereby Increasing Its Activity

Cited by 47 publications

References 62 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

Cbfa1-dependent expression of an interferon-inducible p204 protein is required for chondrocyte differentiation

STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice

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