Leukemia-related transcription factor TEL accelerates differentiation of Friend erythroleukemia cells

Waga, Kazuo; Nakamura, Yūichi; Maki, Kazuhiro; Arai, Honoka; Yamagata, Tetsuya; Sasaki, Ko; Kurokawa, Mineo; Hirai, Hisamaru; Mitani, Kinuko

doi:10.1038/sj.onc.1206072

Cited by 24 publications

(29 citation statements)

References 40 publications

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“…The C-terminal ETV6 mutations were either inframe or resulted in truncation of the ETS domain by out-of-frame mutation. In concordance with earlier studies (Waga et al, 2003;Wood et al, 2003), the truncated ETV6 proteins were impaired in repressing transcription in a ETV6-specific luciferase assay. Moreover, coexpression of the mutants with an intact homodimerization domain (#2236, 3102, 2649 and N) completely abolished the transcription repression by wt ETV6.…”

Section: Discussionsupporting

confidence: 76%

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Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

et al. 2005

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ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization-or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.

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Section: Discussionsupporting

confidence: 76%

“…Moreover, ETV6 has been shown to stimulate erythroid differentiation of the murine erythroid leukemia cell line (Waga et al, 2003). ETV6 knockout mice are embryonic lethal at days 10.5-11.5 and exhibit defects in yolk sac angiogenesis and intraembryonic apoptosis of mesenchymal and neural cells.…”

Section: Introductionmentioning

confidence: 99%

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

et al. 2005

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“…The expression of plasmid pCXN2-FLAG-TEL was described in a previous study. (20) To establish stable transfectants, 1 × 10 7 of UT-7/GM cells were electroporated with 20 µg of pCXN2-FLAG-TEL at 380 V and 975 µF using Gene Pulser (Bio-Rad, Hercules, CA). Transfected cells were selected with 0.8 mg/mL of G418 (Sigma-Aldrich, St. Louis, MO) and cloned by limiting dilution.…”

Section: Methodsmentioning

confidence: 99%

“…(19) As for lineage-specific roles in hematopoietic systems, we have reported that TEL accelerates erythroid differentiation of mouse erythroleukemia (MEL) cells induced by hexamethylene bisacetamide (HMBA) or dimethylsulfoxide (DMSO). (20) Because both erythroblasts and megakaryocytes arise from common progenitors, this observation prompted us to search for TEL's roles in lineage commitment of the bi-potential progenitors.…”

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confidence: 99%

TEL/ETV6 accelerates erythroid differentiation and inhibits megakaryocytic maturation in a human leukemia cell line UT‐7/GM

et al. 2005

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T EL (also known as ETV6) is a member of the E26 transformation-specific (ETS) family of transcription factors.(1) The highly conserved ETS domain is located at the Cterminal region, while a distinct domain with weak homology to the well-described helix-loop-helix (HLH) domain (also referred to as the pointed domain) is located at the N-terminal region. The former serves for DNA binding to the ETS-binding consensus site (EBS) (GGAA/ T) and the latter for homodimerization and heterodimerization with other ETS family members.(2,3) Through interacting with relevant corepressors mSin3A, N-CoR and SMRT, and histone deacetylase-3, (4) TEL mediates transcriptional repression on its target genes such as FLI-1,inhibitor of differentiation / DNA binding-1 (Id-1), (5) stromelysin-1 (6) and Bcl-X L .(7) Transcriptional activities of TEL are regulated through phosphorylation with mitogen-activated protein kinases (8,9) and small ubiquitin-like modifier conjugation. (10,11) The TEL gene that is mapped to 12p13 is most frequently rearranged and fused to various partner genes by chromosomal translocations in human leukemias and myelodysplastic syndromes. The partners include receptor type or non-receptor type tyrosine kinases and transcription factors. Providing tyrosine kinases, such as platelet-derived growth factor receptor β (PDGFRβ) in t(5;12) (q33;p13), (12) ABL1 in t(9;12) (q34;p13),ARG (ABL2) in t(1;12) (q25;p13), (14) JAK2 in t(9;12) (p24;p13) (15) and Syk in t(9;12) (q22;p13), (16) with the HLH domain, TEL homodimerizes them and thereby stimulates their kinase activities. In contrast, TEL gives corepressor-binding domains to a transcription factor AML1 in t(12;21) (p13;q22) and interferes with its transcriptional abilities.(17) Therefore, dysregulation of the partner proteins by TEL functional domains seems to cause leukemia in patients with 12p13 translocations. Moreover, inactivation of the TEL gene is speculated to be the second hit in t(12;21) (p13;q22) type leukemia, because the wild-type-TEL allele is deleted in the vast majority of the patients. (18,19) Thus, TEL appears to be a tumor suppressor. Consistent with its roles as a putative tumor suppressor, expression of TEL in Ras-transformed NIH3T3 cells inhibits cell growth in liquid and soft agar cultures, (6) and in serum-starved NIH3T3 cells induces apoptosis. (6)

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“…Such dual effects, transactivation or repression of different target genes by one transcription factor, have previously been described for other transcription factors likewise among which are members of the ETS family (65)(66)(67)(68)(69)(70)(71)94).…”

Section: Discussionmentioning

confidence: 99%

Regulation of protein tyrosine kinases in tumour cells by the transcription factor Ets-1

Hahne

Kummer²,

Heukamp³

et al. 2009

Int J Oncol

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Abstract. Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication. The family of tyrosine kinases (PTKs) are responsible for part of the cellular phosphorylation and are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis and survival under physiological as well as pathological conditions. Aberration in PTK signalling occurs in inflammatory diseases and diabetes, and aberrant expression can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogenes and proto-oncogenes involved in cancer code for PTKs. Therefore, these enzymes are now used as targets in the treatment of different tumours. Ets-1 is a transcription factor expressed in a number of human malignancies with demonstrated roles within both neoplastic cells and tumour stroma. These roles include stimulation of tumour cell proliferation and invasion as well as tumour angiogenesis. Database searches have revealed that ETS binding sites are present in several promoters of PTK-encoding genes. We investigated the role of Ets-1 in transcriptional regulation of a panel of 89 PTKs in epithelial HeLa tumour cells. In this study, HeLa cells stably overexpressing and underexpressing Ets-1 were used for real-time PCR analysis of all known human PTKs. The results suggest that Ets-1 is an essential transcription factor that cannot be substituted by other members of the ETS family. Transcription of most PTKs was found to be increased by Ets-1. In contrast Ets-1 seems to act as a transcriptional repressor of other PTKs. The data presented here underscore the importance of Ets-1 in tumour development and progression.

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Leukemia-related transcription factor TEL accelerates differentiation of Friend erythroleukemia cells

Cited by 24 publications

References 40 publications

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

TEL/ETV6 accelerates erythroid differentiation and inhibits megakaryocytic maturation in a human leukemia cell line UT‐7/GM

Regulation of protein tyrosine kinases in tumour cells by the transcription factor Ets-1

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