Tel, a Frequent Target of Leukemic Translocations, Induces Cellular Aggregation and Influences Expression of Extracellular Matrix Components

Rompaey, Luc Van; Dou, Wenjie; Buijs, Arjan; Grosveld, Gerard

doi:10.1038/sj.neo.7900064

Cited by 18 publications

(19 citation statements)

References 41 publications

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“…TEL Impairs the Formation of Focal Adhesions-ETS family members are regulators of ECM remodeling, and TEL influences the expression of several ECM genes including fibronectin and the matrix metalloproteinase Stromelysin-1 (33,36). In addition, the cellular aggregation phenotype observed upon TEL expression can be reverted when the cells are cultured on dishes coated with either fibronectin or the extracellular matrix component type IV collagen (33).…”

Section: Resultsmentioning

confidence: 99%

“…TEL Induces Apoptosis-Expression of TEL in Ras-transformed NIH 3T3 cells caused cell aggregation and decreased cell growth (33)(34)(35)(36). Alterations in cell growth can be attributed to a slowing of the cell cycle or increased cell death.…”

Section: Resultsmentioning

confidence: 99%

“…deacetylase 3 (29 -32). The biological role of TEL in normal cell growth is still unclear, but its repressor activity is required for TEL to inhibit the growth of Ras-transformed NIH 3T3 cells and to induce cellular aggregation (33)(34)(35)(36). One target gene directly repressed via TEL is the matrix metalloproteinase 3 gene, Stromelysin-1 (36).…”

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confidence: 99%

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TEL, a Putative Tumor Suppressor, Induces Apoptosis and Represses Transcription of Bcl-XL

Irvin¹,

Wood²,

Wang³

et al. 2003

Journal of Biological Chemistry

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TEL (translocation-Ets-leukemia or ETV6) was originally identified at the breakpoint of the t(5;12) in patients with chronic myelomonocytic leukemia (1). Chromosomal rearrangements that disrupt TEL lead to a variety of myeloid and lymphoid leukemias, and the proteins fused to TEL can be divided into two broad categories: protein tyrosine kinases or transcription factors. In t(5;12) and t(9;12) the N terminus of TEL is fused to platelet-derived growth factor ␤ or the tyrosine kinase ABL, respectively (1, 2). The Pointed domain located within the N terminus of TEL induces dimerization and subsequent activation of the tyrosine kinases (3-5). In these cases, aberrant regulation of the kinase activity of the fusion proteins is a contributing factor to leukemogenesis.On the other hand, fusions of TEL with transcription factors can either retain or eliminate the DNA binding activity of TEL. The t(12;22) fuses the transcription factor MN1 to the C-terminal DNA binding domain of TEL, which converts TEL from a repressor to an activator (6, 7). Alternatively, in 25% of pediatric acute lymphoid leukemias the t(12;21) fuses the Nterminal Pointed domain and repressor domains of TEL to nearly all of the AML1

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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TEL, a Putative Tumor Suppressor, Induces Apoptosis and Represses Transcription of Bcl-XL

Irvin¹,

Wood²,

Wang³

et al. 2003

Journal of Biological Chemistry

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“…Whether TEL is involved in Fli-1-mediated repression of the COL1A2 remains to be elucidated. Significantly, however, stable overexpression of TEL in NIH3T3 fibroblasts led to the down-regulation of collagen type I (42).…”

Section: Discussionmentioning

confidence: 99%

Fli-1 Inhibits Collagen Type I Production in Dermal Fibroblasts via an Sp1-dependent Pathway

Czuwara-Ladykowska

Shirasaki

Jackers

et al. 2001

Journal of Biological Chemistry

154

149

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Fibrosis is characterized by the excessive deposition of extracellular matrix (ECM), especially collagen. Because Ets factors are implicated in physiological and pathological ECM remodeling, the aim of this study was to investigate the role of Ets factors in collagen production. We demonstrate that the expression of collagenous proteins and collagen ␣2(I) (COL1A2) mRNA was inhibited following stable transfection of Fli-1 in dermal fibroblasts. Subsequent analysis of the COL1A2 promoter identified a critical Ets binding site that mediates Fli-1 inhibition. In contrast, Ets-1 stimulates COL1A2 promoter activity. In vitro binding assays demonstrate that both Fli-1 and Ets-1 form DNA-protein complexes with sequences present in COL1A2 promoter. Furthermore, Fli-1 binding to the COL1A2 is enhanced via Sp1-dependent interaction. Studies using Fli-1 dominant interference and DNA binding mutants indicate that Fli-1 inhibition is mediated by both direct (DNA binding) and indirect (via protein-protein interaction) mechanisms and that Sp1 is an important mediator of the Fli-1 function. Furthermore, experiments using the Gal4 system in the context of different cell types as well as experiments with the COL1A2 promoter in different cell lines demonstrate that the direction and magnitude of the effect of Fli-1 is promoter-and cell context-specific. We propose that Fli-1 inhibits COL1A2 promoter activity by competition with Ets-1. In addition, we postulate that another factor (co-repressor) may be required for maximal inhibition after recruitment to the Fli-1-Sp1 complex. We conclude that the ratio of Fli-1 to Ets-1 and the presence of co-regulatory proteins ultimately control ECM production in fibroblasts.

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“…TELnull embryonic stem cells did not contribute to the adult bone marrow in chimeric mice, suggesting a defect in cell migration or cell adhesion of stem cells (Wang et al, 1997(Wang et al, , 1998. In addition, when TEL was expressed in Ras-transformed NIH3T3 cells, TEL inhibited cell growth (Fenrick et al, 2000;Van Rompaey et al, 2000) and induced cellular aggregation (Fenrick et al, 2000;Van Rompaey et al, 1999). TEL also repressed the expression of stromelysin-1 (Fenrick et al, 2000), an extracellular matrix metalloproteinase (MMP) that remodels the extracellular matrix (Lochter et al, 1997;Wiesen and Werb, 1996).…”

Section: Introductionmentioning

confidence: 99%

TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3

Wang

Hiebert

2001

Oncogene

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TEL (Translocation ± ETS ± Leukemia or ETV 6) is disrupted by multiple chromosomal translocations in acute leukemia. The loss of heterozygosity at the TEL locus in leukemias and the hemizygous deletion of TEL that is observed in various tumors, suggests that TEL is a tumor suppressor. Overexpression of TEL alters cellular morphology and represses the expression of the matrix metalloproteinase stromelysin-1. Based on these studies, deletion analysis was used to de®ne the minimal repression domains of TEL. TEL-mediated repression required both the N-terminal pointed domain and a central region composed of amino acids 268 ± 303. The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively. Unexpectedly, histone deacetylase-3, but not other histone deacetylases, also associates with the central region of TEL. Histone deacetylase-3 interacts with a TEL mutant that cannot bind N-CoR, suggesting that this is a direct interaction with TEL. In addition, histone H3 was under-acetylated near the TEL-binding sites in the endogenous stromelysin-1 promoter when TEL was expressed. Furthermore, trichostatin A, a potent histone deacetylase inhibitor, impaired TELdependent repression of the stromelysin-1 promoter. Finally, while TEL-expression induced cellular aggregation of Ras-transformed cells, Trichostatin A reversed the TEL-induced cellular aggregation phenotype. Thus, the cumulative data suggests that histone deacetylase-3 activity is required for the transcriptional functions of TEL. Oncogene (2001) 20, 3716 ± 3725.

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Tel, a Frequent Target of Leukemic Translocations, Induces Cellular Aggregation and Influences Expression of Extracellular Matrix Components

Cited by 18 publications

References 41 publications

TEL, a Putative Tumor Suppressor, Induces Apoptosis and Represses Transcription of Bcl-XL

TEL, a Putative Tumor Suppressor, Induces Apoptosis and Represses Transcription of Bcl-XL

Fli-1 Inhibits Collagen Type I Production in Dermal Fibroblasts via an Sp1-dependent Pathway

TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3

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