A
            <i>RUNX2/PEBP2</i>
            αA/
            <i>CBFA1</i>
            mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia

Zhang, Kun; Yasui, Natsuo; Ito, Kosei; Huang, Gang; Fujii, Makiko; Hanai, Jun‐ichi; Nogami, Hiroshi; Ochi, Takahiro; Miyazono, Kohei; Ito, Yoshiaki

doi:10.1073/pnas.180309597

Cited by 316 publications

(308 citation statements)

References 41 publications

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“…(22) Here we repeated the assay in MC3T3-E1 cells, and the data showed that the overexpression of Runx2 alone activated the reporter vector (3-to 4-fold) and that overexpression of CHIP significantly blunted the activity of Runx2 (Fig. 5A).…”

Section: Mir-764-5p Upregulates the Runx2 Activity By Regulating Chipmentioning

confidence: 85%

miR-764-5p promotes osteoblast differentiation through inhibition of CHIP/STUB1 expression

Guo

Ren

Wang

et al. 2012

Journal of Bone and Mineral Research

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Differentiation of committed precursor cells into the osteoblast lineage is tightly regulated by several factors, including Runx2 and BMP2. We previously reported that C terminus of Hsc70-interacting protein/STIP1 homology and U-Box containing protein 1 (CHIP/STUB1) negatively regulated osteoblast differentiation through promoting Runx2 protein degradation. However, how CHIP is regulated during osteoblast differentiation remains unknown. In this study, we found that miR-764-5p is up-expressed during the osteoblast differentiation in calvarial and osteoblast progenitor cells, coupled with down-expression of CHIP protein. We observed that forced expression or inhibition of miR-764-5p decreased or increased the CHIP protein level through affecting its translation by targeting the 3 0 -UTR region. Perturbation of miR-764-5p resulted in altered differentiation fate of osteoblast progenitor cells and the role of miR-764-5p was reversed by overexpression of CHIP, whereas depletion of CHIP impaired the effect of miR-764-5p. Our data showed that miR-764-5p positively regulates osteoblast differentiation from osteoblast progenitor cells by repressing the translation of CHIP protein. ß

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Section: Mir-764-5p Upregulates the Runx2 Activity By Regulating Chipmentioning

confidence: 85%

miR-764-5p promotes osteoblast differentiation through inhibition of CHIP/STUB1 expression

Guo

Ren

Wang

et al. 2012

Journal of Bone and Mineral Research

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“…In addition to transcriptional regulation by BMP2, Runx2 physically interacts with Smad proteins to form active transcriptional complexes for osteogenic gene expression, resulting in the synergy between Runx2 and BMP2. 62,63 Therefore, we hypothesize that NELL-1 may augment BMP2/Smad osteogenesis by stimulating canonical Wnt signaling and promoting Runx2.…”

Section: Proposed Molecular Mechanisms Of Nell-1 and Bmp2 Effects On mentioning

confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

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“…Loss of runx2 leads to severe abrogation of bone development (reviewed in Karsenty, 2008). Genes such as osteocalcin, osteopontin, col10, and smad6, which are involved in osteoblast formation, are all directly regu-lated by binding of Runx2 together with Smad1 on the promoters of these genes (Zhang et al, 2000;Drissi et al, 2003;Wang et al, 2007). Because both Runx2 and BMP signaling are critical for development of these cell types, these data suggest that Runx2 may widely coordinate the expression of BMP target genes involved in osteoblast differentiation.…”

Section: Transcription Factor Partners For Smads In the Regulation Ofmentioning

confidence: 99%

Finding partners: How BMPs select their targets

Blitz

Cho

2009

Developmental Dynamics

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The bone morphogenetic protein (BMP) signaling pathway is a conserved and evolutionarily ancient regulatory module affecting a large variety of cellular behaviors. The evolutionary flexibility in using BMP responses presumably arose by co-option of a canonical BMP signaling cascade to regulate the transcription of diverse batteries of target genes. This begs the question of how seemingly interchangeable BMP signaling components elicit widely different outputs in different cell types, an important issue in the context of understanding how BMP signaling integrates with gene regulatory networks to control development. Because a molecular understanding of how BMP signaling activates different batteries of target genes is an essential prerequisite to comprehending the roles of BMPs in regulating cellular responses, here we review the current knowledge of how BMP-regulated target genes are selected by the signal transduction machinery. We highlight recent studies suggesting the evolutionary conservation of BMP target gene regulation signaling by Schnurri family zinc finger proteins.

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A RUNX2/PEBP2 αA/ CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia

Cited by 316 publications

References 41 publications

miR-764-5p promotes osteoblast differentiation through inhibition of CHIP/STUB1 expression

miR-764-5p promotes osteoblast differentiation through inhibition of CHIP/STUB1 expression

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Finding partners: How BMPs select their targets

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