The Tissue-Specific Nuclear Matrix Protein, NMP-2, Is a Member of the AML/PEBP2/Runt Domain Transcription Factor Family: Interactions with the Osteocalcin Gene Promoter

Merriman, Harold L.; Wijnen, André J. van; Hiebert, Scott W.; Bidwell, Joseph P.; Fey, Edward G.; Lian, Jane B.; Stein, Janet L.

doi:10.1021/bi00040a025

Cited by 240 publications

(223 citation statements)

References 41 publications

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“…PEBP2/CBF␣ family members (also termed polyoma virus enhancer binding protein 2, or PEBP2␣; and acute myelogenous leukemia factors; Refs. 19 -21) were previously identified in nuclear extracts from differentiated osteoblasts and found to have a critical role in the expression of the osteoblast-related protein, osteocalcin (18,42,43). Our studies with the TGF-␤RI have now identified a new target for PEBP2/CBF␣ activity beyond the virus-infected or immunological tissues where their identity was first established (19).…”

Section: Fig 10mentioning

confidence: 60%

Multiple and Essential Sp1 Binding Sites in the Promoter for Transforming Growth Factor-β Type I Receptor

Casinghino

McCarthy

et al. 1997

Journal of Biological Chemistry

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Maximal gene expression driven by the promoter for the transforming growth factor ␤ type I receptor (TGF-␤RI) occurs with a 1.0-kilobase pair fragment immediately upstream of exon 1. This region lacks a typical TATA box but contains CCAAT boxes, multiple Sp1, and PEBP2/CBF␣ binding sites among other possible cis-acting elements. Alterations within two CCAAT box sequences do not mitigate reporter gene expression driven by the basal promoter, and no nuclear factor binds to oligonucleotides encompassing these sites. In contrast, other deletions or site-specific mutations reveal an essential Sp1 site in the basal promoter and several dispersed upstream Sp1 sites that contribute to maximal reporter gene expression. The proportions of transcription factors Sp1 and Sp3, and their ratios of binding to consensus elements, are maintained in bone cells at different stages of differentiation. Finally, nuclear factor that binds to PEBP2/CBF␣-related cis-acting elements in the basal promoter sequence also occurs in osteoblasts. Our studies reveal that constitutive expression of TGF-␤RI may be determined by constitutive nuclear factor binding to Sp1 sites, whereas other elements may account for the variations in TGF-␤RI levels that parallel changes in bone cell differentiation or activity.Transforming growth factor-␤ (TGF-␤) 1 receptors occur on most cells, and a functional TGF-␤ type I receptor (TGF-␤RI) is required for all known TGF-␤-dependent effects. In some situations its activity is controlled by complex interactions with other cell surface components (1-3). However, in contrast to TGF-␤RII and the cell surface proteoglycan also termed TGF-␤RIII or betaglycan, expression of TGF-␤RI is maintained on differentiated bone cells (4). For these reasons, and because little is known about the molecular control of TGF-␤RI expression, we cloned the rat TGF-␤RI promoter and characterized several of its functional aspects in cultures of primary and continuous skeletal and nonskeletal cells derived from fetal rats. The rat TGF-␤RI promoter lacks a typical TATA box, but initiates transcription at multiple sites within a 220-bp span upstream of the initial methionine codon in differentiated bone cells. The 3Ј-terminal 300-bp sequence encompassing this region contains a GC-rich CpG island, seven consensus Sp1 binding sites, and two CCAAT boxes. Transfection studies using different fragments of TGF-␤RI promoter cloned upstream of the reporter gene luciferase demonstrated maximal activity by a 1.0-kb fragment that encompassed these and other possible cis-acting elements. Importantly, several dispersed elements appeared to cooperate for maximal reporter gene expression in osteoblast-enriched cultures (5). Coincident with this work, the human TGF-␤RI promoter was cloned, and its sequence reveals a similar organization with identically spaced CCAAT box motifs (6).These features suggested that the TGF-␤RI gene is driven by a constitutively active promoter that maintains expression of TGF-␤RI in many cells. Nevertheless, this promoter is part...

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Section: Fig 10mentioning

confidence: 60%

Multiple and Essential Sp1 Binding Sites in the Promoter for Transforming Growth Factor-β Type I Receptor

Casinghino

McCarthy

et al. 1997

Journal of Biological Chemistry

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“…After signalinduced activation, these proteins interact with transcription factors and act on target genes (1)(2)(3)(4). A broad range of nuclear proteins including tissue-restricted transcription factors (e.g., Runx proteins), chromatin-remodeling complexes (e.g., SWI͞ SNF), components of basal transcription machinery (e.g., active form of RNA Pol II), and proteins involved in RNA processing (e.g., SC35) exhibit distinct subnuclear distributions (5)(6)(7)(8). The subnuclear organization of these regulatory complexes may determine their optimal functions.…”

Section: Ammalian Cells Respond To a Vast Array Of Extracellularmentioning

confidence: 99%

Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites

Zaidi

Sullivan

Wijnen

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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174

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Runx factors control lineage commitment and are transcriptional effectors of Smad signaling. Genetic defects in these pathways interfere with normal development. The in situ localization of Runx and Smad proteins must impact the mechanisms by which these proteins function together in gene regulation. We show that the integration of Runx and Smad signals is mediated by in situ interactions at specific foci within the nucleus. Activated Smads are directed to these subnuclear foci only in the presence of Runx proteins. Smad-Runx complexes are associated in situ with the nuclear matrix, and this association requires the intranuclear targeting signal of Runx factors. The convergence of Smad and Runx proteins at these sites supports transcription as reflected by BrUTP labeling and functional cooperativity between the proteins. Thus, Runx-mediated intranuclear targeting of Smads is critical for the integration of two distinct pathways essential for fetal development.M ammalian cells respond to a vast array of extracellular signals that play a critical role in determining cell fate. These regulatory signals are often transmitted to the nucleus by proteins capable of nucleocytoplasmic shuttling. After signalinduced activation, these proteins interact with transcription factors and act on target genes (1-4). A broad range of nuclear proteins including tissue-restricted transcription factors (e.g., Runx proteins), chromatin-remodeling complexes (e.g., SWI͞ SNF), components of basal transcription machinery (e.g., active form of RNA Pol II), and proteins involved in RNA processing (e.g., SC35) exhibit distinct subnuclear distributions (5-8). The subnuclear organization of these regulatory complexes may determine their optimal functions. Mechanisms underlying the activation of signaling proteins and their nuclear translocation have been extensively studied (1-4). It remains elusive whether the biological activities of these proteins require assembly of regulatory complexes within distinct subnuclear domains.Runx factors exhibit a tissue-restricted pattern of expression and are required for definitive hematopoiesis and osteoblast maturation (9-12). Runx proteins have recently been shown to interact through their C-terminal segment with Smads, a family of signaling proteins that regulate a diverse array of developmental and biological processes in response to transforming growth factor (TGF)-␤͞bone morphogenetic protein (BMP) family of growth factors (1, 13-16). The C terminus of Runx proteins also mediates interactions with coregulators like Yesassociated protein (17) and groucho͞TLE proteins (18). Moreover, subnuclear distribution of Runx proteins is mediated by the nuclear matrix-targeting signal, a protein motif present in the C terminus of Runx factors (19)(20)(21)(22). Importantly, in vivo osteogenesis requires the C terminus of Runx2 containing the overlapping subnuclear targeting signal and the Smad interacting domain (23). The Runx and Smad proteins are jointly involved in the regulation of phenotypic gene expression a...

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“…Overexpression of Runx2 and osterix in engineered MSCs may direct osteoblastic lineage differentiation and suppress other lineage differentiation (Merriman et al, 1995;Nakashima et al, 2002). Runx2-engineered MSCs directly enhance the repair of critical-sized calvarial defects when implanted solely (Zheng et al, 2004;Zhao et al, 2007) and form more bone when used in BTE (Zhao et al, 2005;Byers et al, 2006).…”

Section: Taz Sox9mentioning

confidence: 99%

Genetically Engineered Mesenchymal Stem Cells: The Ongoing Research for Bone Tissue Engineering

Hong

Chen²,

et al. 2010

The Anatomical Record

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Bone grafting is crucial in the surgical treatment of bone defects and nonunion fractures. Autogenous bone, allogenous bone, and biomaterial scaffold are three main sources of bone grafts. The biomaterial scaffold, both natural and synthetic, is widely accessible but weak in osteogenic potential. One approach to solve this problem is cell-based bone tissue engineering (BTE), established by growing living osteogenic cells on scaffold in vitro to build up its osteoinducitive capability. Mesenchymal stem cell (MSC) is suitable for use in cell-based BTE, but it remains a considerable challenge to induce MSCs to form solely bone and while preventing MSCs from differentiating into fats, muscles, and possibly neural elements in vivo. Recently, there is a drastic rise in use of genetically engineered MSCs, which can secrete growth factors or alter the transcription level, leading to osteoblast lineage commitment, bone formation, fracture repair, and spinal fusion. In this article, we reviewed the literatures regarding applications of genetically engineered MSCs in BTE. We addressed the currently applicable genes and candidate genes for MSCs modification, transduction efficiency and safety issues of the transfect vectors, and administration routes, and we briefly described in vivo tracking and potential clinical application of the genetically modified MSCs in BTE. Anat Rec, 293:531-537, 2010. V V C 2009 Wiley-Liss, Inc.

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The Tissue-Specific Nuclear Matrix Protein, NMP-2, Is a Member of the AML/PEBP2/Runt Domain Transcription Factor Family: Interactions with the Osteocalcin Gene Promoter

Cited by 240 publications

References 41 publications

Multiple and Essential Sp1 Binding Sites in the Promoter for Transforming Growth Factor-β Type I Receptor

Multiple and Essential Sp1 Binding Sites in the Promoter for Transforming Growth Factor-β Type I Receptor

Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites

Genetically Engineered Mesenchymal Stem Cells: The Ongoing Research for Bone Tissue Engineering

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