Structure and regulated expression of mammalian RUNX genes

Levanon, Ditsa; Groner, Yoram

doi:10.1038/sj.onc.1207670

Cited by 250 publications

(266 citation statements)

References 125 publications

Supporting

Mentioning

259

Contrasting

Order By: Relevance

“…The Runx1 P1 promoter contains three consensus binding sites for RUNX (ACCACA), and its activity was increased Ϸ2.5-fold by cotransfecting a Runx1 expression plasmid (Fig. 5Cii), consistent with a predicted autoregulatory loop (19). Cotransfection with either Smad6 or Smurf1 alone did not result in a significant reduction of Runx1-mediated luciferase activity, but cotransfection with Smad6 and Smurf1 reduced Runx1 mediated luciferase activity to baseline (Fig.…”

Section: Smad6 and Smad1mentioning

confidence: 54%

The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity

Pimanda

Donaldson

Bruijn

et al. 2007

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

111

104

View full text Add to dashboard Cite

Hematopoietic stem cell (HSC) development is regulated by several signaling pathways and a number of key transcription factors, which include Scl/Tal1, Runx1, and members of the Smad family. However, it remains unclear how these various determinants interact. Using a genome-wide computational screen based on the well characterized Scl ؉19 HSC enhancer, we have identified a related Smad6 enhancer that also targets expression to blood and endothelial cells in transgenic mice. Smad6, Bmp4, and Runx1 transcripts are concentrated along the ventral aspect of the E10.5 dorsal aorta in the aorta-gonad-mesonephros region from which HSCs originate. Moreover, Smad6, an inhibitor of Bmp4 signaling, binds and inhibits Runx1 activity, whereas Smad1, a positive mediator of Bmp4 signaling, transactivates the Runx1 promoter. Taken together, our results integrate three key determinants of HSC development; the Scl transcriptional network, Runx1 activity, and the Bmp4/Smad signaling pathway.hematopoiesis ͉ SMAD6 ͉ hematopoietic stem cell ͉ aorta-gonad-mesonephros ͉ bioinformatics T he coordinated expression of genes lies at the heart of metazoan development, with complex gene-regulatory networks governing the spatial variation and temporal sequence with which genes are expressed (reviewed in ref. 1). Transcription factors and the cis-regulatory sequences to which they bind form the building blocks of gene-regulatory networks (2). Recognizing the components and hierarchy of gene-regulatory networks and their interactions with cell-signaling pathways not only provides insights into biology but also is fundamental to understanding how deregulation of networks contributes to pathology.In the postgenomics era, classical methods to screen for potential gene-regulatory regions, such as DNase I hypersensitivity mapping by Southern blotting of selected loci, are being superseded by new genome-wide techniques such as ChIP coupled to genomic tiling arrays (ChIP/chip) (3)or high-throughput sequencing of sequence tags indicating DNase I hypersensitivity (4). Although these largescale screening techniques may rapidly identify the positions of large numbers of candidate regulatory elements, they do not accurately predict their function, i.e., whether a given element is an enhancer or silencer, nor the pattern of activity in cell types other than those analyzed. Moreover, the large amounts of biological material required prevent use of these techniques in the study of early developmental programs and adult stem cell systems. Consequently, in silico approaches are increasingly used to perform genome-wide identification of candidate regulatory elements. Transcription factors often act as components of multiprotein complexes binding to clusters of binding sites. Well characterized regulatory modules with known combinations of transcription factor-binding sites can greatly facilitate the in silico prediction of other cis-regulatory modules that may be important in regulating the same biological process. This method is proving to be a powerful tool in ...

show abstract

Section: Smad6 and Smad1mentioning

confidence: 54%

The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity

Pimanda

Donaldson

Bruijn

et al. 2007

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

111

104

View full text Add to dashboard Cite

show abstract

“…IRES-dependent translation adds an additional level at which expression of this gene is regulated. The two translational mechanisms can provide the flexibility needed for production of the protein in the appropriate amount at the proper time and in the right cell type as has been shown for Runx1 (Pozner et al, 2000;Levanon and Groner, 2004). Therefore, Runx2 translation through different mechanisms might explain the discrepancy between Runx2 protein and mRNA expression levels after TGF-b1 or BMP2 treatment.…”

Section: Discussionmentioning

confidence: 96%

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

et al. 2007

View full text Add to dashboard Cite

Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-b1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (Po0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-b1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-b1 and BMP2 in an auto-and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment.

show abstract

“…However, within the promoter and intron-1 regions, the 2DL5B*00602 differs substantially from 2DL5B*00601 and displays the highest homology with the expressed allele 2DL5B*003 ( Figure 2b). As seen in all 2DL5A sequences and 2DL5B*003, an acute myeloid leukemia gene 1 (AML1) site in the promoter region (also known as CBP, CBFa, PEBP2 or RUNX), 19,20 the factor that has been implicated for KIR2DL5 expression is intact in 2DL5B*00602 alleles, and therefore this allele is likely to be expressed on the cell surface. As the 2DL5B*00602 is a rare allele (identified in just one of the 248 KIR2DL5-positive individuals) and lymphocytes from this individual were not available, we could not confirm the cell surface expression of 2DL5B*00602.…”

Section: Discovery Of Nine Novel Kir2dl5 Sequencesmentioning

confidence: 99%

KIR2DL5 alleles mark certain combination of activating KIR genes

Sharma

Spellman

et al. 2008

Genes Immun

View full text Add to dashboard Cite

Killer cell Ig-like receptors (KIR) control the immune response of NK cells and some T cells to infections and tumors. KIR genes evolve rapidly and are variable between individuals in their number, type and sequence. Here, we determined the nature of KIR2DL5 gene polymorphism in four ethnic groups using direct DNA sequencing method. Nine new sequences were discovered. Within the panel of 248 KIR2DL5-positive individuals, 14 KIR2DL5-sequences differing in coding regions were observed. They differed at only seven amino acid positions, and such limited polymorphism is consistent with its conserved nature throughout the hominoid lineage. Ethnic deviation was seen in the distribution of KIR2DL5A, KIR2DL5B and their alleles. African Americans had more KIR2DL5 alleles than other populations indicating that more polymorphisms are yet to be discovered in Africans. Linkage between KIR2DL5-alleles and certain activating-KIR genes were observed, but frequency of these linked clusters differed substantially between populations. Consequently, KIR2DL5 alleles can be used as markers to predict the activating-KIR gene content. Typing system distinguishing A*001 and B*002 alleles can serve as a powerful screening test to assess the content of most variable activating-KIR genes that have been implicated in human disease and in the outcome of hematopoietic stem cell transplantation.

show abstract

Structure and regulated expression of mammalian RUNX genes

Cited by 250 publications

References 125 publications

The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity

The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

KIR2DL5 alleles mark certain combination of activating KIR genes

Contact Info

Product

Resources

About