Role of RUNX family members in transcriptional repression and gene silencing

Durst, Kristie L.; Hiebert, Scott W.

doi:10.1038/sj.onc.1207122

Cited by 165 publications

(156 citation statements)

References 49 publications

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“…It has been reported that RUNX3 interacts with mSin3 and Groucho/TLE, which associate with HDACs, and SUV39H1, a histone methyltransferase, to inhibit or silence the gene transcription (Durst and Hiebert, 2004). The two binding sites for RUNX3 that we identified on Akt1 promoter are adjacent to the STAT3-binding motifs and b-catenin/ TCF-binding elements.…”

Section: Discussionmentioning

confidence: 65%

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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Section: Discussionmentioning

confidence: 65%

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

et al. 2012

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“…It should be pointed out that Runx1 seems to be a relatively weak activator of transcription, given that DNA binding of Runx1/CBF-b on its own is necessary but insufficient to exert full activation of gene transcription (Durst and Hiebert, 2004). Thus, it was proposed that Runx1 functions as an organizing protein that facilitates assembly of transcriptional activation complexes (Kurokawa and Hirai, 2003).…”

Section: Discussionmentioning

confidence: 99%

Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1α

et al. 2007

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Angiogenesis and hematopoiesis are closely linked and interactive with each other, but few studies were given to identify possible links between angiogenesis-promoting proteins and hematopoiesis-related transcription factors. Here we investigated the potential relationship of oxygensensitive a-subunit of angiogenesis-related hypoxiainducible factor-1a (HIF-1a) with Runt-related protein 1 (Runx1, also known as acute myeloid leukemia-1, AML-1), an important hematopoietic transcription factor. The results demonstrated that Runx1 and HIF-1a proteins directly interacted with each other to a degree, in which Runt homology domain of Runx1 was mainly involved. Leukemia-related abnormal Runx1 fusion protein AML1-ETO, which fuses the N-terminal 177 amino acid residues of the Runx1 protein in frame to ETO (eight-twenty-one) protein, also interacted with HIF-1a protein with greater ability than Runx1 itself. More intriguingly, Runx1 overexpression inhibited DNA-binding and transcriptional activity of HIF-1 protein with reduced expression of HIF-1-targeted genes such as vascular endothelial growth factor, while silence of Runx1 expression by specific small interfering RNA significantly increased transcriptional activity of HIF-1 protein, suggesting that Runx1 inhibited transcription-dependent function of HIF-1. Vice versa, HIF-1a increased DNA-binding ability and transcriptional activity of Runx1 protein. All these data would shed new insight to understanding Runx1 and HIF-1a-related hematopoietic cell differentiation and angiogenesis.

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“…Upon binding regulatory regions of target genes, AML1 has been suggested to facilitate the assembly of protein complexes involved in both transcriptional activation and repression, in a cell type-specific manner Durst and Hiebert, 2004). Thus AML1 can either repress or activate the p21 WAF-1 promoter depending on cell type.…”

Section: Domain Analysis Of Tel-aml1 M Morrow Et Almentioning

confidence: 99%

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

Morrow

Samanta

Kioussis³

et al. 2007

Oncogene

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The t(12;21)(p13;q22) translocation generates the TEL-AML1 (TEL, translocation-Ets-leukemia; AML1, acute myeloid leukemia-1) (ETV6-RUNX1) fusion product and is the most common chromosomal abnormality in pediatric leukemia. Our previous studies using a murine fetal liver transplantation model demonstrated that TEL-AML1 promotes the self-renewal of B-cell precursors in vitro and enhances the expansion of hematopoietic stem cells (HSCs) in vivo. This is consistent with the hypothesis that TEL-AML1 induces expansion of a preleukemic clone. Several studies have described domains within TEL-AML1 involved in the transcriptional regulation of specific target genes. However, it is unclear which of these domains is important for the activity of TEL-AML1 in preleukemic hematopoiesis. In order to examine this, we have generated a panel of deletion mutants and expressed them in HSCs. These experiments demonstrate that TEL-AML1 requires multiple domains from both TEL and AML1 to alter hematopoiesis. Furthermore, mutation of a single amino-acid residue within the runt homology domain of AML1, required for DNA binding, was sufficient to abrogate TEL-AML1 activity. These data suggest that TEL-AML1 acts as an aberrant transcription factor to perturb multiple pathways during hematopoiesis.

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Role of RUNX family members in transcriptional repression and gene silencing

Cited by 165 publications

References 49 publications

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

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

Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1α

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

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