The transcriptional regulator Yin Yang 1 activates the myelin PLP gene

[Objective] Transcriptional control of inflammation-relevant genes plays an important role in atherosclerosis. We have reported a dominant role of Yin Yang 1 (YY1), a transcriptional regulator, in proliferation of vascular smooth muscle cells (Santiago FS, Ishii H, et al. Circ Res in press). However, its effect in vascular endothelium remains unclear. Recent observation points a novel “genomic” effect of Angiotensin II to influence inflammation. In this study, we examined a potential contribution of YY1 in angiotensin type II receptor blocker (ARB)-mediated modulation of leukocyte-endothelial adhesion under flow condition. [Methods and Results] Human umbilical vein endothelial cells (HUVEC) were co-incubated in the presence or absence of candesartan, an ARB (1 uM) for 4 hours with TNFα (5 ng/ml). Treatment with candesartan dramatically inhibited THP-1 cell adhesion to TNFα-activated HUVEC under static (p <0.01) and flow conditions (p <0.05). We documented that upregulation of YY1 mRNA after candesartan treatment. To examine a role for YY1 in leukocyte-endothelial interaction, YY1 was overexpressed via recombinant adenovirus. The expression levels of VCAM-1 was significantly decreased in HUVEC treated with adenovirus YY1. In addition, adenovirus YY1 blocked THP-1 adhesion to TNFα-activated HUVEC under flow conditions (TNFα, 8.40±0.64/HPF; TNFα+candesartan, 1.93±0.54/HPF; p <0.0001). The expression level of phosphorylated-JNK, as determined by western blotting analysis, was reduced following YY1 transfection. In contrast, YY1 inhibition by YY1 siRNA did not influence leukocyte-endothelial adhesion and the expression of adhesion molecules. [Conclusion] We demonstrated that candesartan treatment upregulated YY1 in HUVEC and inhibited leukocyte-endothelial adhesion by inhibition of VCAM-1 expression. Our findings suggest a novel anti-inflammatory effect of ARB via YY1-dependent mechanisms.

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The gene encoding the transcriptional regulator Yin Yang 1 (YY1) is a myeloid transforming gene interfering with neutrophilic differentiation

Blood ◽

10.1182/blood-2002-04-1207 ◽

2003 ◽

Vol 101 (3) ◽

pp. 1111-1117 ◽

Cited By ~ 34

Author(s):

Stefan J. Erkeland ◽

Marijke Valkhof ◽

Claudia Heijmans-Antonissen ◽

Ruud Delwel ◽

Peter J. M. Valk ◽

...

Keyword(s):

Bone Marrow Cells ◽

Transcriptional Start Site ◽

Leukemia Virus ◽

Transcriptional Regulator ◽

Luciferase Reporter ◽

Insertion Mutagenesis ◽

Gene Encoding ◽

Protein Levels ◽

Yin Yang 1 ◽

Yin Yang

AbstractThe genetic defects underlying the pathogenesis of acute myeloid leukemia (AML) are still largely unknown. Retroviral insertion mutagenesis in mice has become a powerful tool to identify candidate genes involved in the development of leukemia and lymphoma. We have used this strategy with the 1.4 strain of Graffi murine leukemia virus (MuLV), which predominantly causes myeloid leukemias. Here, we report that Graffi-1.4–induced AML frequently harbors virus integrations in the gene encoding the transcription factor Yin Yang 1 (YY1). These integrations occurred in both orientations, and all were located in the 5′ promoter region of the gene, 0.5 to 1.5 kb upstream of the major transcriptional start site. Luciferase reporter assays showed that virus integration in this region increases promoter activity and renders it independent of a functional binding site for Sp1, a major transcriptional regulator of YY1. We used the murine 32D model to study the consequence of perturbed YY1 expression for myelopoiesis. YY1 protein levels were high in 32D parental cells maintained in interleukin-3–containing medium, but they dropped when the cells were induced to differentiate by granulocyte–colony-stimulating factor (G-CSF). Strikingly, G-CSF–induced neutrophilic differentiation was reduced in 32D cell transfectants ectopically expressing YY1. In similar experiments on primary bone marrow cells, enforced YY1 expression blocked the outgrowth of CFU-GM colonies. Increased YY1 expression was seen in some cases of human AML. Collectively, these data imply a possible role of perturbed expression of YY1 in the development of AML through interference with the myeloid differentiation program in the leukemic progenitor cells.

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