Abstract

Aberrant TGF-beta function has been implicated in the pathogenesis of many diseases, and it has also suggested that diminished responsiveness to TGF-beta may contribute to the process of malignant transformation. This decreased responsiveness to TGF-beta could be caused by defects not only in TGF-beta expression of activation, but also by defects in the regulation of TGF-beta receptors. Transcriptional repression of the TGF-beta type II receptor (RII) is one of the mechanisms leading to TGF-beta resistance. The newly identified epithelium-specific ets transcription factor ERT/ESX/ESE-1/ELF3/jen binds to the TGF-beta RII promoter and induces promoter activity. The human gastric cancer cell lines, which show no detectable levels of TGF-beta RII mRNA do not express ERT mRNAs. To study the molecular mechanisms of loss of ERT expression, we have cloned and characterized the human ERT promoter. We have identified a distinct positive regulatory element (-186 to -175). The positive regulatory element interacts with four distinct nuclear protein complexes, at least one of which appears to be absent in cell lines which do not express the ERT mRNA. Deletion of the positive regulatory element markedly decreased expression of the target gene, suggesting that loss of the sequence-specific DNA binding protein is responsible for the loss of ERT expression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005617-12
Application #
6433044
Study Section
(LCRC)
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2000
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Lee, H-J; Yun, C-H; Lim, S H et al. (2007) SRF is a nuclear repressor of Smad3-mediated TGF-beta signaling. Oncogene 26:173-85
Lucas, Philip J; Kim, Seong-Jin; Mackall, Crystal L et al. (2006) Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. Blood 108:2789-95
Kim, Byung-Gyu; Li, Cuiling; Qiao, Wenhui et al. (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015-9
Choi, Kyung-Chul; Lee, Youn Sook; Lim, Seunghwan et al. (2006) Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1. Nat Immunol 7:1057-65
Zhang, Qiang; Yang, Ximing J; Kundu, Shilajit D et al. (2006) Blockade of transforming growth factor-{beta} signaling in tumor-reactive CD8(+) T cells activates the antitumor immune response cycle. Mol Cancer Ther 5:1733-43
Zhang, Qiang; Jang, Thomas L; Yang, Ximing et al. (2006) Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells. Prostate 66:235-47
Minguillon, Jordi; Morancho, Beatriz; Kim, Seong-Jin et al. (2005) Concentrations of cyclosporin A and FK506 that inhibit IL-2 induction in human T cells do not affect TGF-beta1 biosynthesis, whereas higher doses of cyclosporin A trigger apoptosis and release of preformed TGF-beta1. J Leukoc Biol 77:748-58
Ryu, Ji-Kan; Song, Sun U; Han, Jee-Young et al. (2005) Establishment of penile fibrosis model in a rat using mouse NIH 3T3 fibroblasts expressing transforming growth factor beta1. Biol Reprod 72:916-21
Kim, Isaac Yi; Kim, Moses M; Kim, Seong-Jin (2005) Transforming growth factor-beta : biology and clinical relevance. J Biochem Mol Biol 38:1-8
Jin, Wook; Kim, Byung-Chul; Tognon, Cristina et al. (2005) The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-beta signaling by inactivating the TGF-beta type II receptor. Proc Natl Acad Sci U S A 102:16239-44

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