Molecular basis of tissue‐specific gene expression mediated by the Runt domain transcription factor PEBP2/CBF

Ito, Yoshiaki

doi:10.1046/j.1365-2443.1999.00298.x

Cited by 162 publications

(147 citation statements)

References 75 publications

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“…AML-2 has been implicated in the activation of the Ig␣ heavy chain gene in B lymphocytes (54). Several alternatively spliced isoforms of AML-1 have been identified (52). This may explain why the N-terminal and C-terminal Abs to AML-1 were differentially reactive in the supershift/blocking assay (Fig.…”

Section: Discussionmentioning

confidence: 99%

Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-α/Dad1 Gene Locus

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et al. 2001

The Journal of Immunology

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Locus control regions (LCRs) refer to cis-acting elements composed of several DNase I hypersensitive sites, which synergize to protect transgenes from integration-site dependent effects in a tissue-specific manner. LCRs have been identified in many immunologically important gene loci, including one between the TCRδ/TCRα gene segments and the ubiquitously expressed Dad1 gene. Expression of a transgene under the control of all the LCR elements is T cell specific. However, a subfragment of this LCR is functional in a wide variety of tissues. How a ubiquitously active element can participate in tissue-restricted LCR activity is not clear. In this study, we localize the ubiquitously active sequences of the TCR-α LCR to an 800-bp region containing a prominent DNase hypersensitive site. In isolation, the activity in this region suppresses position effect transgene silencing in many tissues. A combination of in vivo footprint examination of this element in widely active transgene and EMSAs revealed tissue-unrestricted factor occupancy patterns and binding of several ubiquitously expressed transcription factors. In contrast, tissue-specific, differential protein occupancies at this element were observed in the endogenous locus or full-length LCR transgene. We identified tissue-restricted AML-1 and Elf-1 as proteins that potentially act via this element. These data demonstrate that a widely active LCR module can synergize with other LCR components to produce tissue-specific LCR activity through differential protein occupancy and function and provide evidence to support a role for this LCR module in the regulation of both TCR and Dad1 genes.

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Section: Discussionmentioning

confidence: 99%

Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-α/Dad1 Gene Locus

Ortiz

Harrow

Cado

et al. 2001

The Journal of Immunology

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“…RUNX2 is a DNA-binding transcription factor that interacts with the promoters of specific target genes (Ito, 1999;Zelzer et al, 2001). To determine whether RUNX2 activity was involved in EC proliferation, endogenous RUNX2 DNA binding was measured by electrophoretic mobility-shift assay (EMSA) in proliferating (subconfluent) and growth-arrested (postconfluent) EC (Figure 4a, b).…”

Section: Runx2 Dna-binding Activity and Ec Proliferationmentioning

confidence: 99%

“…The Runx genes are a conserved family of DNAbinding proteins containing a unique Runt homology domain (RHD) originally described in Drosophila (Ito, 1999). The RUNX proteins are members of the Ig-loop DNA-binding family of proteins that include Stat1, p53, and nuclear factor-kB (NF-kB) (Bravo et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Regulation of TGFβ1-mediated growth inhibition and apoptosis by RUNX2 isoforms in endothelial cells

et al. 2004

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Runx transcription factors regulate viral growth, hematopoiesis, bone formation, angiogenesis, and gastric epithelial development through specific DNA-binding motifs on target gene promoters. Vascular endothelial cells (ECs) express RUNX genes that are activated by angiogenic factors. The RUNX2 gene also activates the vascular endothelial growth factor promoter. Alternatively spliced forms of RUNX genes have been described, but their functions in angiogenesis have not been elucidated. In this study, expression of a novel alternatively spliced variant of RUNX2 (RUNX2D8), lacking the region encoded by exon 8, was detected in aortic tissue undergoing angiogenesis in vitro and in ECs. Expression of RUNX2 and RUNX2D8 increased in vascular sprouts concomitant with expression of cellular proteases and cytokines known to mediate angiogenesis. RUNX2 DNA-binding activity was expressed in proliferating but not quiescent ECs. Ectopic expression of RUNX2 in ECs increased cell sprouting, cell proliferation, DNA synthesis, and phosphorylation of phosphorylated retinoblastoma relative to control transfectants while RUNX2, but not RUNX2D8 transfectants, acquired resistance to growth inhibition by transforming growth factor (TGFb 1 ). Furthermore, RUNX2D8-transfected cells were more sensitive to TGFb 1 -induced apoptosis than RUNX2 transfectants. Consistent with these data, the RUNX2 gene was a strong repressor of the promoter of the cyclin-dependent kinase inhibitor, p21 CIP1 , while RUNX2D8 was a competitive inhibitor of RUNX2 and exhibited weak repression activity. These results support the hypothesis that ECs regulate growth and apoptosis, in part, by alternative splicing events in the RUNX2 transcription factor to affect the TGFb 1 signaling pathway. The exon 8 domain of RUNX2 may contribute to the strong repression activity of RUNX2 for some target gene promoters.

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“…The human RUNX gene (the runt-related transcription factor) is the homologue from the Drosophila genes runt (Kania et al, 1990) and lozenge (Daga et al, 1996) and contains highly conserved sequence of 'runt domain', which directs the binding of RUNX protein to DNA via protein-protein interaction with the partner protein CBFb and mediates the transcription activation or repression of the targeted genes (Ito, 1999). The human RUNX family includes three members: RUNX1/ AML1, RUNX2/CBFA1 and RUNX3/PEBP2aC/ AML2.…”

Section: Introductionmentioning

confidence: 99%

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

et al. 2012

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Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream b-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused b-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.

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Molecular basis of tissue‐specific gene expression mediated by the Runt domain transcription factor PEBP2/CBF

Cited by 162 publications

References 75 publications

Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-α/Dad1 Gene Locus

Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-α/Dad1 Gene Locus

Regulation of TGFβ1-mediated growth inhibition and apoptosis by RUNX2 isoforms in endothelial cells

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

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