Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis

Huang, Xuling; Brown, Courtney; Ni, Weihua; Maynard, Elizabeth; Rigby, Alan C.; Oettgen, Peter

doi:10.1182/blood-2005-08-3206

Cited by 46 publications

(51 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taking advantage of the structural similarities between the subfamilies in the DNA-binding domain of ETS1 and ETS2, it is possible to inhibit both oncogenes in KS or neoangiogenic blood vessels at the same time using a common therapeutic agent. 39 We also found by gene profiling that miR-221 and miR-222 share redundant activities involving the targeting of common mRNAs. Overall, 39% of miR-222-regulated genes, including BCL6, C14orf4, CXCR4, HEY1, KIAA1946, LMBRD1, NDRG1, PELO, and SMPDL3A, are also the targets of miR-221 ( Figure 4C).…”

Section: Discussionmentioning

confidence: 76%

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

Wu¹,

Hu²,

Chen³

et al. 2011

Blood

View full text Add to dashboard Cite

miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is upregulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNAmRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting IntroductionKaposi sarcoma-associated herpesvirus (KSHV) was identified in 1994. 1 KSHV is also associated with 2 other human B-cell leukemias, primary effusion lymphoma (PEL) and multicentric Castleman disease. 2 Kaposi sarcoma (KS) is one of the few human cancers derived from a lymphatic endothelial cell (LEC) lineage, 3,4 and typically appears as colored lesions or patches on the skin, although it can spread to internal organs. 2 This disease has been recognized as a highly disseminated and angiogenic tumor. 4 Analyzing KSHV clonality at different stages of KS has shown that KS begins as a polyclonal disease and then evolves into a mono/oligoclonal disease involving infected spindle cells. 5 This model therefore implies that the spreading of a few malignant spindle cells in patients' bodies occurs during tumor progression. Moreover, distal metastasis, such as pulmonary KS, can be observed in AIDS-KS patients and causes diffused lung disease. Tumor cells of KSHV-associated B-cell neoplasias (PEL and multicentric Castleman disease) are also able to migrate into body cavities. 6 The ability of KSHV to induce cell migration and invasion is therefore important to disease progression.In vitro, KSHV infects both micro-and macrovascular endothelial cells (ECs), and these cells are useful when studying the role of KSHV in the pathogenesis of KS. 7,8 KSHV has also become a powerful tool that aids in the study of EC biology. 9 KSHV infects both LECs and blood vessel ECs (BECs) of microvascular origin in vitro. 3,4 After infection, KSHV stimulates EC invasiveness by inducing extracellular matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, and MMP-9. 10 Because the majority of cells in KS lesions and in KSHV-infected...

show abstract

Section: Discussionmentioning

confidence: 76%

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

Wu¹,

Hu²,

Chen³

et al. 2011

Blood

View full text Add to dashboard Cite

show abstract

“…It has been previously shown possible to inhibit ETS factors in whole animal models without any harm coming to normal tissue (Huang et al, 2006). As high LMO2 removal is sufficient to cause death of leukaemic cells even after acquisition of secondary genetic abnormalities (Appert et al, 2009), identification of the molecular mechanisms involved in aberrant ectopic expression of LMO2 may open up new targeted therapeutic options directed towards the impediment of upstream regulators to block the maintenance of the leukaemia phenotype.…”

Section: Discussionmentioning

confidence: 99%

A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

et al. 2010

View full text Add to dashboard Cite

The T-cell oncogene Lim-only 2 (LMO2) critically influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic expression is seen in the majority of T-acute lymphoblastic leukaemia (T-ALL) patients with specific translocations involving LMO2 in only a subset of these patients. Ectopic lmo2 expression in thymocytes of transgenic mice causes T-ALL, and retroviral vector integration into the LMO2 locus was implicated in the development of clonal T-cell disease in patients undergoing gene therapy. Using array-based chromatin immunoprecipitation, we now demonstrate that in contrast to B-acute lymphoblastic leukaemia, human T-ALL samples largely use promoter elements with little influence from distal enhancers. Active LMO2 promoter elements in T-ALL included a previously unrecognized third promoter, which we demonstrate to be active in cell lines, primary T-ALL patients and transgenic mice. The ETS factors ERG and FLI1 previously implicated in lmo2-dependent mouse models of T-ALL bind to the novel LMO2 promoter in human T-ALL samples, while in return LMO2 binds to blood stem/progenitor enhancers in the FLI1 and ERG gene loci. Moreover, LMO2, ERG and FLI1 all regulate the þ 1 enhancer of HHEX/PRH, which was recently implicated as a key mediator of early progenitor expansion in LMO2-driven T-ALL. Our data therefore suggest that a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as HHEX/PRH.

show abstract

“…15,16 Additional details are provided in the expanded Materials and Methods section in the online data supplement.…”

Section: Western Blot Analysismentioning

confidence: 99%

Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47 ^phox Gene Expression in Response to Angiotensin II

Ni¹,

Zhan²,

He³

et al. 2007

Circulation Research

Self Cite

View full text Add to dashboard Cite

Abstract-Angiotensin (Ang) II is a potent mediator of vascular inflammation. A central mechanism by which Ang II promotes inflammation is through the generation of reactive oxygen species (ROS). In the current study, we investigated the role of the transcription factor Ets-1 in regulating Ang II-induced ROS generation. ROS generation was measured in the thoracic aorta of Ets-1 Ϫ/Ϫ mice compared with littermate controls after continuous infusion of Ang II. H 2 O 2 and superoxide anion (O 2 Ϫ ) production were significantly blunted in the Ets-1 Ϫ/Ϫ mice. Inhibition of Ets-1 expression by small interfering RNA in primary human aortic smooth muscle cells also potently inhibited ROS production and the induction of the NAD(P)H oxidase subunit p47 phox in response to Ang II. To evaluate the therapeutic potential of inhibiting Ets-1 in wild-type mice, dominant negative Ets-1 membrane-permeable peptides were administered systemically. Ang II-induced ROS production and medial hypertrophy in the thoracic aorta were markedly diminished as a result of blocking Ets-1. In summary, Ets-1 functions as a critical downstream transcriptional mediator of Ang II ROS generation by regulating the expression of NAD (P)

show abstract

Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis

Cited by 46 publications

References 35 publications

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47 ^phox Gene Expression in Response to Angiotensin II

Contact Info

Product

Resources

About

Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis

Cited by 46 publications

References 35 publications

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47 phox Gene Expression in Response to Angiotensin II

Contact Info

Product

Resources

About

Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47 ^phox Gene Expression in Response to Angiotensin II