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Results for “Core Binding Factor alpha Subunits”

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At least 19 recordsLinked to original sources

PubMed2000

Biophysical characterization of interactions between the core binding factor alpha and beta subunits and DNA.

Core binding factors (CBFs) play key roles in several developmental pathways and in human disease. CBFs consist of a DNA binding CBFalpha subunit and a non-DNA binding CBFbeta subunit that increases the affinity of CBFalpha for DNA. We performed sedimentation equilibrium analyses to unequivocally establish the stoichiometry of the CBFalpha:beta:DNA complex. Dissociation constants for all four equilibria involving the CBFalpha Runt domain, CBFbeta, and DNA were defined. Conformational changes associated with interactions between CBFalpha, CBFbeta, and DNA were monitored by nuclear magnetic resonance and circular dichroism spectroscopy. The data suggest that CBFbeta 'locks in' a high affinity DNA binding conformation of the CBFalpha Runt domain.

Animals↗

PubMed1999

Solution structure of core binding factor beta and map of the CBF alpha binding site.

The core binding factor beta subunit (CBF beta) is the non-DNA binding subunit of the core-binding factors, transcription factors essential for multiple developmental processes including hematopoiesis and bone development. Chromosomal translocations involving the human CBFB gene are associated with a large percentage of human leukemias. The N-terminal 141 amino acids of CBF beta contains the heterodimerization domain for the DNA-binding CBF alpha subunits, and is sufficient for CBF beta function in vivo. Here we present the high-resolution solution structure of the CBF beta heterodimerization domain. It is a novel alpha/beta structure consisting of two three-stranded beta-sheets packed on one another in a sandwich arrangement, with four peripheral alpha-helices. The CBF alpha binding site on CBF beta has been mapped by chemical shift perturbation analysis.

Binding Sites↗

PubMed1995

A new transcription factor family associated with human leukemias.

The proteins known as the polyoma enhancer binding protein 2 or core-binding factor (PEBP2/CBF) are heterodimeric transcription factors that contain a DNA-binding subunit (CBF alpha), and a subunit that does not bind DNA independently (CBF beta). PEBP2 and CBF were identified independently as proteins that regulate transcription of viral and cellular enhancers, and also as proteins whose genes are disrupted by chromosomal abnormalities in human leukemias. This review traces the history of the discovery of the PEBP2 and CBF protein family and describes the biochemical properties of the normal and oncogenic forms of these proteins.

Amino Acid Sequence↗

PubMed2004

Homologs of RUNX and CBF beta/PEBP2 beta in C. elegans.

RUNX proteins are evolutionarily well-conserved transcription factors that are involved in essential aspects of the development of metazoan animals ranging from nematodes to humans. Genetic or epigenetic defects in any one of the three RUNX proteins in humans cause severe diseases. Although much is known about the functions and signaling pathways of the RUNX proteins through the use of mammalian systems, there are still gaps in our knowledge with regard to the functions of the RUNX proteins in normal development and disease states. Recently, the nematode Caenorhabditis elegans was revealed to bear one RUNX homolog (RNT-1) and one homolog of the RUNX protein partner CBF beta/PEBP2 beta (BRO-1). The expression patterns and biological functions of RNT-1 and the manner in which it is regulated are all comparable to what has been observed for the mammalian RUNX proteins. Thus, the nematode system is a promising model system for elucidating the functions and regulation of Runt proteins. In addition, it has recently emerged that the RNT-1 protein is involved in a transforming growth factor beta signaling pathway. The bro-1 gene encoding the CBF beta homolog is exclusively expressed in the hypodermis, not in the intestine, which indicates that additional tissue-specific cofactors in the intestine might exist. The possible autoregulation of RNT-1 expression by RNT-1/BRO-1 in the hypodermal cells is also discussed.

Animals↗

PubMed1994

AML1 is expressed in skeletal muscle and is regulated by innervation.

Although most skeletal muscle genes are expressed at similar levels in electrically active, innervated muscle and in electrically inactive, denervated muscle, a small number of genes, including those encoding the acetylcholine receptor, N-CAM, and myogenin, are expressed at significantly higher levels in denervated than in innervated muscle. The mechanisms that mediate electrical activity-dependent gene regulation are not understood, but these mechanisms are likely to be responsible, at least in part, for the changes in muscle structure and function that accompany a decrease in myofiber electrical activity. To understand how muscle activity regulates muscle structure and function, we used a subtractive-hybridization and cloning strategy to identify and isolate genes that are expressed preferentially in innervated or denervated muscle. One of the genes which we found to be regulated by electrical activity is the recently discovered acute myeloid leukemia 1 (AML1) gene. Disruption and translocation of the human AML1 gene are responsible for a form of acute myeloid leukemia. AML1 is a DNA-binding protein, but its normal function is not known and its expression and regulation in skeletal muscle were not previously appreciated. Because of its potential role as a transcriptional mediator of electrical activity, we characterized expression of the AML1 gene in innervated, denervated, and developing skeletal muscle. We show that AML1 is expressed at low levels in innervated skeletal muscle and at 50- to 100-fold-higher levels in denervated muscle. Four AML1 transcripts are expressed in denervated muscle, and the abundance of each transcript increases after denervation. We transfected C2 muscle cells with an expression vector encoding AML1, tagged with an epitope from hemagglutinin, and we show that AML1 is a nuclear protein in muscle. AML1 dimerizes with core-binding factor beta (CBF beta), and we show that CGF beta is expressed at high levels in both innervated and denervated skeletal muscle. PEBP2 alpha, which is structurally related to AML1 and which also dimerizes with CBF beta, is expressed at low levels in skeletal muscle and is up-regulated only weakly by denervation. These results are consistent with the idea that AML1 may have a role in regulating gene expression in skeletal muscle.

Animals↗

PubMed2003

Upstream and downstream targets of RUNX proteins.

In recent years, the in vivo role of the three members of the RUNX family of transcription factors has in part been elucidated. While Runx1 is essential for mature haematopoiesis and Runx2 for osteochondrogenesis, Runx3 has a function in the nervous system. Translocations and mutations affecting the RUNX1 gene are clearly implicated in leukemogenesis whereas recent data suggest that changed expression levels of RUNX3 may be involved in gastric carcinogenesis. Germ line mutations in RUNX2 have been identified in patients with an autosomal dominant skeletal disorder, cleidocranial dysplasia. While a number of pathways have been delineated that regulate RUNX activity, transcription factors binding to RUNX promoters are only beginning to be identified. A growing number of genes have been characterised that are being regulated in their transcriptional activity by different RUNX proteins. Whether a particular RUNX protein specifically targets a defined subset of downstream genes or whether there is some redundancy as to which RUNX protein activates which target promoter remains to be elucidated.

Animals↗

PubMed2001

Identification and comparative analysis of a second runx3 promoter.

The runx gene family encodes transcriptional regulators that are essential in several processes. Alternative transcription start sites (3' or P1 and 5' or P2) have been described both at runx1 and runx2. Functional domains have been mapped to P2 N-termini. Here, starting from an analysis of cDNA clones, we identify a P2 promoter at mouse runx3. In functional assays in COS-7 cells, this promoter is as active as runx1 P2. By nuclease protection, primer extension and deletion analysis we map a major start site and define a minimal promoter element. The activity of both promoters at all three mouse loci was systematically compared in a comprehensive panel of fresh tissues. The conservation of a two-promoter structure and their distinctive pattern of activity support the hypothesis that alternative 5' isoforms subserve unique functions.

Animals↗

PubMed2002

Expression of Runx1, -2 and -3 during tooth, palate and craniofacial bone development.

We describe the expression of three Runt-related RUNX genes (previously termed AML, Cbfa, or Pebp2alpha) Runx1 and Runx3 during the development of teeth and other craniofacial tissues and compare them to Runx2 expression reported earlier. All three genes were expressed in mesenchymal condensates. Runx1 was expressed in several cartilage primordia earlier than Runx3, and Runx2 was intense in all mesenchymal condensations of bones and teeth. Only Runx1 was expressed in epithelia, and in tooth germs transcripts were detected in outer dental epithelium. Runx1 was also intensely expressed in the midline epithelium of palatal shelves. In early tooth morphogenesis Runx3 was coexpressed with Runx2 in a thin layer of mesenchymal cells underlying dental epithelium. Unlike Runx2, Runx3 was expressed in odontoblasts. However, Runx3 mutant mice did not show obvious tooth phenotype or deviations of Runx1 and Runx2 expression patterns in the tooth.

Animals↗

PubMed2003

RUNX transcription factors as key targets of TGF-beta superfamily signaling.

The Runt domain transcription factors, RUNX1, RUNX2 and RUNX3, are integral components of signaling cascades mediated by both TGF-beta and bone morphogenetic proteins (BMPs) in several important biological systems. RUNX2 functions synergistically with Smad1 and Smad5 to regulate bone-specific genes when BMP induces osteogenesis. RUNX3, which has been mapped to locus 1p36, is a major tumor suppressor of gastric cancer and appears to be an important component of the TGF-beta-induced tumor suppressor pathway. A possible relationship between the TGF-beta-induced tumor-suppressor pathway and a postulated tumor suppressor gene on 1p36 must be examined.

Animals↗

PubMed2003

Runx transcription factors and the developmental balance between cell proliferation and differentiation.

The runt box (Runx) is a highly conserved DNA binding and protein-protein interaction domain that defines a family of heterodimeric transcription factors with essential roles in metazoan development. The first member of this family to be identified was the Drosophila regulatory gene runt, which was named by virtue of its function in establishing segmentation patterns during embryogenesis, and subsequently discovered to have additional functions in sex determination and neurogenesis. A second Drosophila Runx gene, lozenge, is required for cell patterning in the eye and for hematopoiesis. The genome project has revealed the existence of two additional Drosophila Runx genes, which to date have not been functionally characterized. Other invertebrate species with well-characterized Runx transcription factors include the nematode Caenorhabditis elegans and the sea urchin Strongylocentrotus purpuratus, each of which apparently contains only a single Runx gene. There are three Runx genes in mammals; Runx1 is required for definitive hematopoiesis and is a frequently mutated gene in human leukemia, Runx2 is required for osteogenesis and is associated with cleidocranial dysplasia, and Runx3 controls neurogenesis in the dorsal root ganglia and cell proliferation in the gastric epithelium, and is frequently deleted or silenced in human gastric cancer. Studies using mammalian systems and sea urchins indicate that Runx proteins have essential functions in both cell proliferation and differentiation, and in mammals they are both proto-oncogenes and tumor suppressors. Thus, a central question concerning the cell biology of Runx proteins is how are the opposing functions of this class of transcription factors regulated during development? Here I review current knowledge of Runx protein structure, function and regulation, and outline directions for future research aimed at understanding how Runx protein function is modulated during the transition from cell proliferation to differentiation in animal development.

Amino Acid Sequence↗

PubMed2004

The Runx genes: lineage-specific oncogenes and tumor suppressors.

The Runx genes present a challenge to the simple binary classification of cancer genes as oncogenes or tumor suppressors. There is evidence that loss of function of two of the three mammalian Runx genes promotes cancer, but in a highly lineage-restricted manner. In human leukemias, the RUNX1 gene is involved in various chromosomal translocation events that create oncogenic fusion proteins, at least some of which appear to function as dominant-negative inhibitors of the normal gene product. Paradoxically, evidence is mounting that structurally intact Runx genes are also oncogenic when overexpressed. All the three murine genes act as targets for transcriptional activation by retroviral insertional mutagenesis, and the oncogenic potential of Runx2 has been confirmed in transgenic mice. Moreover, the RUNX1 gene is often amplified or overexpressed in cases of acute leukemia. The state of progress in elucidating the oncogenic roles of the Runx genes is the subject of this review, and we draw together recent observations in a tentative model for the effects of Runx deregulation on hematopoietic cell differentiation. We suggest that lineage-specific factors determine the sensitivity to the oncogenic effects of loss or overexpression of Runx factors.

Animals↗

PubMed2004

Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins.

Runx proteins regulate various biological processes, including growth and differentiation of hematopoietic cells, lymphocytes, osteoblasts, and gastric epithelial cells. Some of the biological activities of Runx proteins are reminiscent of those of transforming growth factor (TGF)-beta superfamily cytokines. Consistent with this notion, receptor-regulated Smads (R-Smads), signal mediators of the TGF-beta superfamily cytokines, and Runx proteins have been shown to physically interact with each other. R-Smads activated by TGF-beta and Runx proteins cooperatively induce synthesis of IgA in B lymphocytes, and those activated by bone morphogenetic proteins and Runx2 induce osteoblastic differentiation. Moreover, the R-Smad-Runx signaling pathways are regulated by an E3 ubiquitin ligase Smurf1, as well as a signal transducer of interferons, STAT1. Since Runxl and Runx3 are involved in the development of some cancers including acute leukemia and gastric cancer, it will be of interest to examine in detail whether TGF-beta-specific R-Smads and Runx proteins coordinately regulate growth and differentiation of hematopoietic cells and gastric epithelial cells.

Animals↗

PubMed2004

Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression.

We present an overview of Runx involvement in regulatory mechanisms that are requisite for fidelity of bone cell growth and differentiation, as well as for skeletal homeostasis and the structural and functional integrity of skeletal tissue. Runx-mediated control is addressed from the perspective of support for biological parameters of skeletal gene expression. We review recent findings that are consistent with an active role for Runx proteins as scaffolds for integration, organization and combinatorial assembly of nucleic acids and regulatory factors within the three-dimensional context of nuclear architecture.

Bone and Bones↗

PubMed2003

Expression of galectin-3 in skeletal tissues is controlled by Runx2.

The beta-galatoside-specific lectin galectin-3 is expressed in vivo in osteoblasts as well as in epiphyseal cartilage. Here we show that in vitro, galectin-3 expression is up-regulated in the preosteoblastic cell line MC3T3-E1 during the matrix maturation stage of the osteoblast developmental sequence. Expression persists into late differentiation stages when the mature osteoblastic phenotype is established. The skeletal expression pattern of galectin-3 overlaps at many sites with that of the transcription factor Runx2. Runx2 is a key regulator of osteoblast development and necessary for chondrocyte differentiation in the growth plate. Both human and mouse galectin-3 promoters contain putative Runx-binding sites. The constitutive or inducible forced expression of Runx2 is sufficient for the onset of galectin-3 transcription in the mesenchymal precursor cell line C3H10T1/2. Moreover, Runx2 is able to bind to at least two sites in the galectin-3 promoter region. The crucial role of Runx2 was confirmed in Runx2-deficient mice, which are devoid of galectin-3 expression in skeletal cells. The overlapping expression pattern of galectin-3 with the other two members of the Runt family of transcription factors (Runx1 and Runx3) points to a potential regulation of the galectin-3 gene (LGALS3) by these factors in hematopoietic, skin, and dorsal root ganglial cells.

Animals↗

PubMed2002

Expression pattern, regulation, and biological role of runt domain transcription factor, run, in Caenorhabditis elegans.

The Caenorhabditis elegans run gene encodes a Runt domain factor. Runx1, Runx2, and Runx3 are the three known mammalian homologs of run. Runx1, which plays an essential role in hematopoiesis, has been identified at the breakpoint of chromosome translocations that are responsible for human leukemia. Runx2 plays an essential role in osteogenesis, and inactivation of one allele of Runx2 is responsible for the human disease cleidocranial dysplasia. To understand the role of run in C. elegans, we used transgenic run::GFP reporter constructs and a double-stranded RNA-mediated interference method. The expression of run was detected as early as the bean stage exclusively in the nuclei of seam hypodermal cells and lasted until the L3 stage. At the larval stage, expression of run was additionally detected in intestinal cells. The regulatory elements responsible for the postembryonic hypodermal seam cells and intestinal cells were separately located within a 7.2-kb-long intron region. This is the first report demonstrating that an intron region is essential for stage-specific and cell type-specific expression of a C. elegans gene. RNA interference analysis targeting the run gene resulted in an early larva-lethal phenotype, with apparent malformation of the hypodermis and intestine. These results suggest that run is involved in the development of a functional hypodermis and gut in C. elegans. The highly conserved role of the Runt domain transcription factor in gut development during evolution from nematodes to mammals is discussed.

Animals↗

PubMed2004

The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region.

Acute myelogenous leukemia 1 (AML1; runt-related transcription factor 1 [Runx1]) is a member of Runx transcription factors and is essential for definitive hematopoiesis. Although AML1 possesses several subdomains of defined biochemical functions, the physiologic relevance of each subdomain to hematopoietic development has been poorly understood. Recently, the consequence of carboxy-terminal truncation in AML1 was analyzed by the hematopoietic rescue assay of AML1-deficient mouse embryonic stem cells using the gene knock-in approach. Nonetheless, a role for specific internal domains, as well as for mutations found in a human disease, of AML1 remains to be elucidated. In this study, we established an experimental system to efficiently evaluate the hematopoietic potential of AML1 using a coculture system of the murine embryonic para-aortic splanchnopleural (P-Sp) region with a stromal cell line, OP9. In this system, the hematopoietic defect of AML1-deficient P-Sp can be rescued by expressing AML1 with retroviral infection. By analysis of AML1 mutants, we demonstrated that the hematopoietic potential of AML1 was closely related to its transcriptional activity. Furthermore, we showed that other Runx transcription factors, Runx2/AML3 or Runx3/AML2, could rescue the hematopoietic defect of AML1-deficient P-Sp. Thus, this experimental system will become a valuable tool to analyze the physiologic function and domain contribution of Runx proteins in hematopoiesis.

Animals↗

PubMed2004

An enigmatic fourth runt domain gene in the fugu genome: ancestral gene loss versus accelerated evolution.

BACKGROUND: The runt domain transcription factors are key regulators of developmental processes in bilaterians, involved both in cell proliferation and differentiation, and their disruption usually leads to disease. Three runt domain genes have been described in each vertebrate genome (the RUNX gene family), but only one in other chordates. Therefore, the common ancestor of vertebrates has been thought to have had a single runt domain gene. RESULTS: Analysis of the genome draft of the fugu pufferfish (Takifugu rubripes) reveals the existence of a fourth runt domain gene, FrRUNT, in addition to the orthologs of human RUNX1, RUNX2 and RUNX3. The tiny FrRUNT packs six exons and two putative promoters in just 3 kb of genomic sequence. The first exon is located within an intron of FrSUPT3H, the ortholog of human SUPT3H, and the first exon of FrSUPT3H resides within the first intron of FrRUNT. The two gene structures are therefore "interlocked". In the human genome, SUPT3H is instead interlocked with RUNX2. FrRUNT has no detectable ortholog in the genomes of mammals, birds or amphibians. We consider alternative explanations for an apparent contradiction between the phylogenetic data and the comparison of the genomic neighborhoods of human and fugu runt domain genes. We hypothesize that an ancient RUNT locus was lost in the tetrapod lineage, together with FrFSTL6, a member of a novel family of follistatin-like genes. CONCLUSIONS: Our results suggest that the runt domain family may have started expanding in chordates much earlier than previously thought, and exemplify the importance of detailed analysis of whole-genome draft sequence to provide new insights into gene evolution.

Amino Acid Sequence↗

PubMed2004

Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors.

Formation of skeletal elements during embryogenesis and the dynamic remodeling of bone in the adult involve an exquisite interplay of developmental cues, signaling proteins, transcription factors, and their coregulatory proteins that support differentiation of osteogenic lineage cells from the initial mesenchymal progenitor cell to the mature osteocyte in mineralized connective tissue. As regulatory factors continue to be identified, the complexity of the molecular mechanisms that control gene expression in osteoblast lineage cells and drive the osteoblast maturation process are being further appreciated. A central regulator of bone formation is the Runx2 (Cbfa1/AML3) transcription factor which fulfills its role as a master regulatory switch through unique properties for mediating the temporal activation and/or repression of cell growth and phenotypic genes as osteoblasts progress through stages of differentiation. This review examines the multifunctional roles of Runx2 during osteogenesis. Runx2 functions as a "platform protein" that interacts with a spectrum of coregulatory proteins to provide a combinatorial mechanism for integrating cell signaling pathways required for osteoblast differentiation and the tissue-specific regulation of gene expression. In a broader context, it has recently been appreciated that the Runx1 hematopoietic factor and the Runx3 gene associated with neural and gut development are also expressed in the skeleton, although at present our knowledge of their roles in bone formation is limited. Here we discuss the biological functions of Runx factors in promoting cell fate determination and lineage progression, which include (1) regulating gene activation and repression through coregulatory protein interactions and by supporting chromatin remodeling; (2) integrating ECM signaling and cues from developmental, hormonal, and signal transduction pathways by formation of complexes organized in subnuclear domains; and (3) mediating cell growth control. Last, a comprehensive understanding of Runx functions in the skeleton must consider the regulatory mechanisms that control Runx2 transcription and its functional activity through posttranslational modifications.

Cell Differentiation↗