Weakening of the repressive YY-1 site on the thrombospondin-1 promoter via c-Jun/YY-1 interaction

Kang, Jung-Hoon; Chang, Seo-Yoon; Yeom, Dong-Hoon; Kim, Soo‐A; Um, Soo‐Jong; Hong, Kyong-Ja

doi:10.1038/emm.2004.41

Cited by 12 publications

(11 citation statements)

References 27 publications

(31 reference statements)

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“…The combined expression of AP-1 and YY1 enhanced HLJ1 expression by 5.3-fold, compared with a 3-fold increase in HLJ1 expression by either YY1 at the promoter or AP-1 at the enhancer region. The results are consistent with earlier reports that these two transcription factors interact to regulate gene expression (23,24).…”

Section: Discussionsupporting

confidence: 93%

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Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

et al. 2007

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HLJ1 is a novel tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. However, the mechanism of HLJ1 activation is currently unclear. Here, we identify an enhancer segment in the HLJ1 gene at À2,125 to À1,039 bp upstream of the transcription start site. A 50-bp element between À1,492 and À1,443 bp is the minimal enhancer segment, which includes the activator protein 1 (AP-1) site (À1,457 to À1,451 bp), an essential regulatory domain that binds the transcriptional factors FosB, JunB, and JunD. Chromatin immunoprecipitation assays confirm that these AP-1 family members bind to a specific site in the HLJ1 enhancer segment in vivo. Overexpression of either YY1 at promoter or AP-1 at enhancer results in a 3-fold increase in the transcriptional activity of HLJ1. We propose a novel mechanism whereby expression of the tumor suppressor, HLJ1, is upregulated via enhancer AP-1 binding to promoter YY1 and the coactivator, p300, through DNA bending and multiprotein complex formation. The combined expression of AP-1 and YY1 enhances HLJ1 expression by more than five times and inhibits in vitro cancer cell invasion. Elucidation of the regulatory mechanism of HLJ1 expression may facilitate the development of personalized therapy by inhibiting cancer cell proliferation, angiogenesis, and metastasis. [Cancer Res 2007;67(10):4816-26]

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Section: Discussionsupporting

confidence: 93%

“…regulating gene expression (23,24). To establish whether AP-1 interacts directly with YY1 on the HLJ1 gene promoter, we selected JunB and JunD, which evidently stimulate transcriptional activity, for coimmunoprecipitation studies with CL1-0 cell nuclear extracts.…”

Section: Resultsmentioning

confidence: 99%

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

et al. 2007

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“…TSP-1 gene promoter appears to have an inhibitory element between −300 and −750 bp positions, as was reported in two independent studies (34, 89). Shorter promoter deletion constructs are significantly more active, as are the longer constructs, both constitutively and in response to stimuli.…”

Section: Introductionsupporting

confidence: 77%

Invoking the power of thrombospondins: Regulation of thrombospondins expression

Stenina‐Adognravi¹

2014

Matrix Biology

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Increasing evidence suggests critical functions of thrombospondins (TSPs) in a variety of physiological and pathological processes. With the growing understanding of the importance of these matricellular proteins, the need to understand the mechanisms of regulation of their expression and potential approaches to modulate their levels is also increasing. The regulation of TSPs expression is multi-leveled, cell- and tissue-specific, and very precise. However, the knowledge of mechanisms modulating the levels of TSPs is fragmented and incomplete. This review discusses the known mechanisms of regulation of TSPs levels and the gaps in our knowledge that prevent us from developing strategies to modulate the expression of these physiologically important proteins.

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“…Furthermore, transfection of VSMCs with the catalytic domain of PKG (constitutively active PKG) overcame the high glucosemediated decrease in PKG activity, resulting in inhibition of glucose-induced TSP1 expression and TGF-␤ activity. In this study, TSP1 expression and TGF-␤ activity under normal glucose conditions are not regulated by PKG activity, suggesting that basal TSP1 expression is maintained through different mechanisms, such as the involvement of transcription factors YY-1 or ELL (22,53). Taken together, our present studies identify a novel mechanism of high glucose-mediated down- Fig.…”

Section: Discussionmentioning

confidence: 53%

Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-β activity in vascular smooth muscle cells

Wang

Lincoln

Murphy-Ullrich

2010

American Journal of Physiology-Cell Physiology

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Diabetes is a major predictor of in-stent restenosis, which is associated with fibroproliferative remodeling of the vascular wall due to increased transforming growth factor-beta (TGF-beta) action. It is well established that thrombospondin1 (TSP1) is a major regulator of TGF-beta activation in renal and cardiac complications of diabetes. However, the role of the TSP1-TGF-beta pathway in macrovascular diabetic complications, including restenosis, has not been addressed. In mesangial cells, high glucose concentrations depress protein kinase G (PKG) activity, but not PKG-I protein, thereby downregulating transcriptional repression of TSP1. Previously, we showed that high glucose downregulates PKG-I protein expression by vascular smooth muscle cells (VSMCs) through altered NADPH oxidase signaling. In the present study, we investigated whether high glucose regulation of PKG protein and activity in VSMCs similarly regulates TSP1 expression and downstream TGF-beta activity. These studies showed that high glucose stimulates both TSP1 expression and TGF-beta bioactivity in primary murine aortic smooth muscle cells (VSMCs). TSP1 is responsible for the increased TGF-beta bioactivity under high glucose conditions, because treatment with anti-TSP1 antibody, small interfering RNA-TSP1, or an inhibitory peptide blocked glucose-mediated increases in TGF-beta activity and extracellular matrix protein (fibronectin) expression. Overexpression of constitutively active PKG, but not the PKG-I protein, inhibited glucose-induced TSP1 expression and TGF-beta bioactivity, suggesting that PKG protein expression is insufficient to regulate TSP1 expression. Together, these data establish that glucose-mediated downregulation of PKG levels stimulates TSP1 expression and enhances TGF-beta activity and matrix protein expression, which can contribute to vascular remodeling in diabetes.

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Weakening of the repressive YY-1 site on the thrombospondin-1 promoter via c-Jun/YY-1 interaction

Cited by 12 publications

References 27 publications

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1

Invoking the power of thrombospondins: Regulation of thrombospondins expression

Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-β activity in vascular smooth muscle cells

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