Genomes and Genes
core binding factor alpha subunits
Summary: A family of transcription factors that bind to the cofactor CORE BINDING FACTOR BETA SUBUNIT to form core binding factor. Family members contain a highly conserved DNA-binding domain known as the runt domain. They can act as both activators and repressors of expression of GENES involved in CELL DIFFERENTIATION and CELL CYCLE progression.
- Vaillant F, Blyth K, Andrew L, Neil J, Cameron E. Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection. J Immunol. 2002;169:2866-74 pubmed..Thus, Runx2 joins a small group of transcription factors that can interfere with early T cell development, cause an expansion of a specific subset, and predispose to lymphoma. ..
- Kagoshima H, Shigesada K, Kohara Y. RUNX regulates stem cell proliferation and differentiation: insights from studies of C. elegans. J Cell Biochem. 2007;100:1119-30 pubmed..In this review, we will outline these new findings and discuss their general implications in the mechanism of coordination between proliferation and differentiation of stem cells. ..
- Stricker S, Fundele R, Vortkamp A, Mundlos S. Role of Runx genes in chondrocyte differentiation. Dev Biol. 2002;245:95-108 pubmed
- Lian J, Javed A, Zaidi S, Lengner C, Montecino M, Van Wijnen A, et al. Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors. Crit Rev Eukaryot Gene Expr. 2004;14:1-41 pubmed..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. ..
- Zhang L, Li Z, Yan J, Pradhan P, Corpora T, Cheney M, et al. Mutagenesis of the Runt domain defines two energetic hot spots for heterodimerization with the core binding factor beta subunit. J Biol Chem. 2003;278:33097-104 pubmed..The importance of the hot spot residues for Runx1 function was demonstrated in in vivo transient transfection assays. These data refine the structural analyses and further our understanding of the Runx1-CBF beta interface. ..
- Ito Y. RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes. Adv Cancer Res. 2008;99:33-76 pubmed..RUNX2 is essential for skeletal development and has an oncogenic potential. RUNX3 is expressed in wider ranges of tissues and has multiple roles. Among others, RUNX3 is a major tumor suppressor of gastric and many other solid tumors. ..
- Tahirov T, Inoue Bungo T, Sasaki M, Shiina M, Kimura K, Sato K, et al. Crystallization and preliminary X-ray analyses of quaternary, ternary and binary protein-DNA complexes with involvement of AML1/Runx-1/CBFalpha Runt domain, CBFbeta and the C/EBPbeta bZip region. Acta Crystallogr D Biol Crystallogr. 2001;57:850-3 pubmed..Complete data sets were collected for all of the native crystals, along with MAD and MIR data sets for CBFalpha-beta-C/EBPbeta-DNA. The heavy-atom site was determined using MAD data for a gold derivative of CBFalpha-beta-C/EBPbeta-DNA. ..
- Tahirov T, Inoue Bungo T, Morii H, Fujikawa A, Sasaki M, Kimura K, et al. Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta. Cell. 2001;104:755-67 pubmed..The point mutations of CBFalpha related to the aforementioned diseases were also mapped and their effect on DNA binding is discussed. ..
- Bao R, Friedrich M. Conserved cluster organization of insect Runx genes. Dev Genes Evol. 2008;218:567-74 pubmed publisher..We propose a model for the conserved cluster organization of developmental gene family paralogs based on differential coduplication of regulatory elements that act over long distances. ..
- Eggers J, Stock M, Fliegauf M, Vonderstrass B, Otto F. Genomic characterization of the RUNX2 gene of Fugu rubripes. Gene. 2002;291:159-67 pubmed..Three further conserved non-coding regions were identified possibly functioning as enhancer elements for tissue-specific expression of RUNX2...
- Ng C, Osato M, Tay B, Venkatesh B, Ito Y. cDNA cloning of Runx family genes from the pufferfish (Fugu rubripes). Gene. 2007;399:162-73 pubmed publisher..The similarities and differences between the Runx family genes of fugu and mammals will improve our understanding of the functions of these proteins...
- Nimmo R, Antebi A, Woollard A. mab-2 encodes RNT-1, a C. elegans Runx homologue essential for controlling cell proliferation in a stem cell-like developmental lineage. Development. 2005;132:5043-54 pubmed..C. elegans is therefore an important model system for studying the biology, and oncogenic potential, of Runx genes. ..
- Otto F, Lubbert M, Stock M. Upstream and downstream targets of RUNX proteins. J Cell Biochem. 2003;89:9-18 pubmed..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. ..
- Sullivan J, Sher D, Eisenstein M, Shigesada K, Reitzel A, Marlow H, et al. The evolutionary origin of the Runx/CBFbeta transcription factors--studies of the most basal metazoans. BMC Evol Biol. 2008;8:228 pubmed publisher..The expression data suggest a hypothesis that these genes may have played a role in nerve cell differentiation or maintenance in the common ancestor of cnidarians and bilaterians...
- Li Z, Yan J, Matheny C, Corpora T, Bravo J, Warren A, et al. Energetic contribution of residues in the Runx1 Runt domain to DNA binding. J Biol Chem. 2003;278:33088-96 pubmed..We propose mechanisms by which mutations in the Runt domain found in hematopoietic and bone disorders affect its affinity for DNA. ..
- Van Wijnen A, Stein G, Gergen J, Groner Y, Hiebert S, Ito Y, et al. Nomenclature for Runt-related (RUNX) proteins. Oncogene. 2004;23:4209-10 pubmed
- Taniuchi I, Littman D. Epigenetic gene silencing by Runx proteins. Oncogene. 2004;23:4341-5 pubmed..These findings link Runx function to epigenetic gene regulation, and shed new light on the mechanisms by which Runx represses target gene expression. ..
- Egawa T, Littman D. ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Nat Immunol. 2008;9:1131-9 pubmed publisher..Our results suggest that MHC class II-selected thymocytes are directed toward the CD4(+) lineage independently of ThPOK but require ThPOK to prevent Runx-dependent differentiation toward the CD8(+) lineage. ..
- Ito Y. Oncogenic potential of the RUNX gene family: 'overview'. Oncogene. 2004;23:4198-208 pubmed..In this Overview, I will summarize how this growing field has been formed and what are the challenging new frontiers for better understanding of the oncogenic potential of this gene family. ..
- Lu J, Maruyama M, Satake M, Bae S, Ogawa E, Kagoshima H, et al. Subcellular localization of the alpha and beta subunits of the acute myeloid leukemia-linked transcription factor PEBP2/CBF. Mol Cell Biol. 1995;15:1651-61 pubmed..The implications of these results in relation to leukemogenesis are discussed. ..
- Tang Y, Shi J, Zhang L, Davis A, Bravo J, Warren A, et al. Energetic and functional contribution of residues in the core binding factor beta (CBFbeta ) subunit to heterodimerization with CBFalpha. J Biol Chem. 2000;275:39579-88 pubmed..These data refine the structural analyses and further support the hypothesis that CBFbeta enhances DNA binding by inducing a conformational change in the Runt domain. ..
- Stock M, Schäfer H, Stricker S, Gross G, Mundlos S, Otto F. Expression of galectin-3 in skeletal tissues is controlled by Runx2. J Biol Chem. 2003;278:17360-7 pubmed
- Rennert J, Coffman J, Mushegian A, Robertson A. The evolution of Runx genes I. A comparative study of sequences from phylogenetically diverse model organisms. BMC Evol Biol. 2003;3:4 pubmed..At least two introns were present in the primordial bilaterian Runx gene. Alternative promoter usage arose prior to the duplication events that gave rise to three Runx genes in vertebrates. ..
- Robertson A, Dickey Sims C, Ransick A, Rupp D, McCarthy J, Coffman J. CBFbeta is a facultative Runx partner in the sea urchin embryo. BMC Biol. 2006;4:4 pubmed publisher..SpCBFbeta is a facultative Runx partner that appears to be required specifically for cell differentiation...
- Ogawa E, Maruyama M, Kagoshima H, Inuzuka M, Lu J, Satake M, et al. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci U S A. 1993;90:6859-63 pubmed..The major species of PEBP2 alpha mRNA was expressed in T-cell lines but not in B-cell lines tested. Evidence indicated that PEBP2 functions as a transcriptional activator and is involved in regulation of T-cell-specific gene expression. ..
- Levanon D, Groner Y. Structure and regulated expression of mammalian RUNX genes. Oncogene. 2004;23:4211-9 pubmed
- Blyth K, Cameron E, Neil J. The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer. 2005;5:376-87 pubmed..have such an ambiguous role in cancer? How and where do these genes impinge on the pathways that regulate growth control and differentiation? And what is the evidence for a wider role for the RUNX genes in non-haematopoietic cancers? ..
- Nam S, Jin Y, Li Q, Lee K, Jeong G, Ito Y, et al. Expression pattern, regulation, and biological role of runt domain transcription factor, run, in Caenorhabditis elegans. Mol Cell Biol. 2002;22:547-54 pubmed..elegans. The highly conserved role of the Runt domain transcription factor in gut development during evolution from nematodes to mammals is discussed. ..
- Leboy P, Grasso Knight G, D ANGELO M, Volk S, Lian J, Drissi H, et al. Smad-Runx interactions during chondrocyte maturation. J Bone Joint Surg Am. 2001;83-A Suppl 1:S15-22 pubmed..These studies demonstrate that both BMP-activated Smads and Runx2 levels can modulate chondrocyte transition to hypertrophy. ..
- Zhong J, Pevny L, Snider W. "Runx"ing towards sensory differentiation. Neuron. 2006;49:325-7 pubmed..These findings emphasize the importance of intrinsic genetic programs in generating the diversity of DRG neurons and specifying the circuits into which they incorporate. ..
- Li Z, Lukasik S, Liu Y, Grembecka J, Bielnicka I, Bushweller J, et al. A mutation in the S-switch region of the Runt domain alters the dynamics of an allosteric network responsible for CBFbeta regulation. J Mol Biol. 2006;364:1073-83 pubmed..This study provides an important functional link between dynamic behavior and protein allosteric function, consistent with results on other allosterically regulated proteins. ..
- Miyazono K, Maeda S, Imamura T. Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins. Oncogene. 2004;23:4232-7 pubmed
- Durst K, Hiebert S. Role of RUNX family members in transcriptional repression and gene silencing. Oncogene. 2004;23:4220-4 pubmed..Thus, transcriptional repression and gene silencing through RUNX1 contribute to the mechanisms of leukemogenesis of the fusion proteins. Therapies directed at the associated cofactors may be beneficial for treatment of these leukemias. ..
- Sun L, Vitolo M, Qiao M, Anglin I, Passaniti A. Regulation of TGFbeta1-mediated growth inhibition and apoptosis by RUNX2 isoforms in endothelial cells. Oncogene. 2004;23:4722-34 pubmed..The exon 8 domain of RUNX2 may contribute to the strong repression activity of RUNX2 for some target gene promoters. ..
- Otto F, Kanegane H, Mundlos S. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Hum Mutat. 2002;19:209-16 pubmed
- Yoshida C, Komori T. Role of Runx proteins in chondrogenesis. Crit Rev Eukaryot Gene Expr. 2005;15:243-54 pubmed..It also highlights how Runx proteins regulate transcription of target genes and how Runx proteins are regulated in the cartilaginous skeleton. ..
- Ito Y, Miyazono K. RUNX transcription factors as key targets of TGF-beta superfamily signaling. Curr Opin Genet Dev. 2003;13:43-7 pubmed..A possible relationship between the TGF-beta-induced tumor-suppressor pathway and a postulated tumor suppressor gene on 1p36 must be examined. ..
- Sato T, Ohno S, Hayashi T, Sato C, Kohu K, Satake M, et al. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity. 2005;22:317-28 pubmed
- Coffman J. Runx transcription factors and the developmental balance between cell proliferation and differentiation. Cell Biol Int. 2003;27:315-24 pubmed
- Komori T. Requisite roles of Runx2 and Cbfb in skeletal development. J Bone Miner Metab. 2003;21:193-7 pubmed..Core binding factor beta (Cbfb) is a cotranscription factor which forms a heterodimer with Runx proteins. Cbfb is required for the functions of Runx1 and Runx2. Thus, Runx2/Cbfb heterodimers play essential roles in skeletal development. ..
- Sun W, Graves B, Speck N. Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins. J Virol. 1995;69:4941-9 pubmed..These findings suggest that ets and cbf proteins cooperate in vivo to regulate transcription from the Mo-MLV and TCR beta enhancers. ..
- Higashikawa A, Kawaguchi H, Nakamura K, Chung U. [Interactions of chondrocytes and osteoblasts during endochondral bone formation]. Clin Calcium. 2006;16:829-36 pubmed
- Truong T, Zhang X, Pathmanathan D, Soo C, Ting K. Craniosynostosis-associated gene nell-1 is regulated by runx2. J Bone Miner Res. 2007;22:7-18 pubmed..These results suggest that Nell-1 is likely a downstream target of Runx2. These findings may also extend our understanding of the molecular mechanisms governing the pathogenesis of craniosynostosis. ..
- Kusumi T, Nishi T, Tanaka M, Tsuchida S, Kudo H. A murine osteosarcoma cell line with a potential to develop ossification upon transplantation. Jpn J Cancer Res. 2001;92:649-58 pubmed..These results suggest that the cell line has the properties of an osteoblastic lineage when cultured in vitro and has an ossifying ability through endochondral bone formation processes when transplanted in vivo. ..
- Barnes G, Javed A, Waller S, Kamal M, Hebert K, Hassan M, et al. Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res. 2003;63:2631-7 pubmed
- Ogawa S, Satake M, Ikuta K. Physical and functional interactions between STAT5 and Runx transcription factors. J Biochem. 2008;143:695-709 pubmed publisher..Thus, this study implies a potential role of the STAT5-Runx interaction in lymphocyte development. ..
- Inoue K, Shiga T, Ito Y. Runx transcription factors in neuronal development. Neural Dev. 2008;3:20 pubmed publisher..As a consequence, Runx contributes to diverse aspects of the sensory system in higher vertebrates. In this review, we summarize recent progress in determining the role of Runx in neuronal development. ..
- Stein G, Stein J, Lian J, van Wijnen A, Montecino M, Javed A, et al. Nuclear microenvironments: an architectural platform for the convergence and integration of transcriptional regulatory signals. Eur J Histochem. 2004;48:65-76 pubmed..We address contributions of nuclear microenvironments to the convergence and integration of regulatory signals that mediate transcription by supporting the combinatorial assembly of regulatory complexes. ..
- Nguyen Khac F, Bernard O. [Chromosomal translocations in human malignant hematopoiesis. Structural and functional consequences]. Pathol Biol (Paris). 2003;51:382-9 pubmed..This work summaries some of the present knowledge regarding human leukemogenesis. ..
- Egawa T, Taniuchi I. Antagonistic interplay between ThPOK and Runx in lineage choice of thymocytes. Blood Cells Mol Dis. 2009;43:27-9 pubmed publisher..Recent studies have revealed that a reciprocal antagonistic interplay between Runx3 and ThPOK is a central component in the transcription factor network governing the helper versus cytotoxic-lineage decision. ..
- Li X, Decker M, Westendorf J. TEThered to Runx: novel binding partners for runx factors. Blood Cells Mol Dis. 2010;45:82-5 pubmed publisher..Potential roles of protein complexes containing FET/TET and RUNX family members during tumor formation and mesenchymal progenitor cell differentiation are discussed. ..