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

Irvin, Brenda J.; Wood, Lauren D.; Wang, Lilin; Fenrick, Randy; Sansam, Courtney G.; Packham, Graham; Kinch, Michael S.; Yang, Elizabeth; Hiebert, Scott W.

doi:10.1074/jbc.m305189200

Cited by 30 publications

(31 citation statements)

References 54 publications

(58 reference statements)

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“…30,31 The inhibitory responses resulted from G 1 arrest or increased apoptosis. 30,32 Furthermore, expression of Tel in Ras-transformed NIH/3T3 cells led to repression of MMP3 transcription and as a result reduced malignancy. 33 These results collectively suggest that Tel acts as a tumor suppressor gene rather than an oncogene.…”

Section: Discussionmentioning

confidence: 99%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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Background: Ets genes encode a family of transcription factors that play key roles in cell proliferation, differentiation and apoptosis. Fusions of Ets genes with other targets have been described in Ewing's sarcoma, chronic myelomonocytic leukemia and more recently prostate carcinoma. Ets expression in breast carcinoma has not been comprehensively studied, and is the focus of this study.Methods: RT-Q-PCR was used to determine the expression of Ets genes in a panel of ten common breast cancer cell lines, two immortalized normal breast epithelial cell lines, and one primary culture of human mammary epithelial cells. Ets with altered expression in cancer cell lines were verified in primary breast tumors.Results: Transcripts of 21 of the 27 Ets genes were detected in either normal or cancer cells. Of the 21 detectable genes, 14 were expressed at a similar level in both normal and breast cancer cell lines. Four genes, Ehf, Elf3, Elf5 and Pdef, were expressed at higher levels in breast cancer cells than normal epithelials. Surprisingly, the expression of Elk3, Ets1 and Fli1 was repressed in breast cancer cells. The protein status of Ehf, Elf3, Pdef, Elk3, Ets1 and Fli1, strongly correlated with the transcript data, suggesting that Ets expression is regulated primarily at the transcriptional level. Similarly, Elf3, Pdef and Tel2 were overexpressed, while Elk3, Ets1 and Fli1 were under-expressed in primary breast tumor specimens in comparison with normal mammary tissues.Conclusions: Our study identified a subset of Ets genes with altered expression in breast carcinoma, implicating their roles in mammary tumorigenesis. While the Ets overexpression pattern is useful to uncover recurrent genetic alterations involving Ets genes, the repressed expression of several Ets genes suggests that some Ets proteins may play suppressor roles during breast cancer progression. Our results warrant detailed studies of individual Ets activity during mammary gland neoplasia.

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Section: Discussionmentioning

confidence: 99%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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“…Thus, deletion of the PTD may compromise the repressor levels recruited to key promoters necessary to interfere with the differentiation program. Alternatively, the PTD may be required for oligomerizing with wt TEL, thereby sequestering the purported tumor suppressor activity of TEL (Fenrick et al, 2000;van Rompaey et al, 2000;Irvin et al, 2003). Further work is required to define the importance of PTD in the TEL/AML1-induced pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model

et al. 2005

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The t(12;21) translocation, generating the TEL/AML1 fusion protein, is the most common genetic lesion in childhood cancer. Using a bone marrow transplantation model, we demonstrate that TEL/AML1 expression impinges on normal hematopoietic differentiation, leading to the in vivo accumulation and persistence of an early progenitor compartment with a Sca1 þ /Kit hi /CD11b þ phenotype and an increased self-renewal capacity, as documented by replating assays in vitro. Differentiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1-transduced progenitors is low. Impaired differentiation is prominently observed in the pro-B-cell compartment, resulting in an proportional increase in early progenitors in vivo, consistent with the t(12;21) ALL phenotype. Despite the accumulation of both multipotent and B-cell progenitors in vivo, no leukemia induction was observed during an observation period of over 1 year. These results are consistent with findings in twins with concordant ALL, showing that TEL/AML1 generates a preleukemic clone in utero that persists for several years in a clinically covert fashion. Furthermore, our studies showed that the pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with either TEL/ AML1 or wild-type TEL, was essential for the observed differentiation impairment and could not be replaced with another oligomerization domain.

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“…Ets-2 is a member of the ETS family of transcription factors that bind to purine-rich DNA sequences with GGA(A/T) as a central core consensus through a highly conserved DNA binding domain (13,14). Ets proteins function as activators or repressors of transcription in partnership with other DNA-binding proteins and coregulators and control the expression of genes involved in diverse biological functions, such as mitosis, growth, development, differentiation, apoptosis, and regulation of immunity (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Ets-2 plays an important role in the maturation, proliferation, and survival of mouse thymocytes, possibly by regulating the expression of c-Myc (23).…”

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confidence: 99%

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes

Panagoulias

Georgakopoulos

Αγγελετοπούλου

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldIL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions.

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

Cited by 30 publications

References 54 publications

Profile of Ets gene expression in human breast carcinoma

Profile of Ets gene expression in human breast carcinoma

Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes

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