Regulation of the TGF-beta type II receptor gene expression by ets family of tra

Kim, Seong Jin

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)
• Support Year: 12
• Fiscal Year: 2000

Institution

• Name: Basic Sciences
• Country: United States

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

Yoo, Byung Moo; Yeo, Marie; Oh, Tae Young et al. (2005) Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling. Pancreas 30:e71-9

Zhang, Qiang; Rubenstein, Jonathan N; Jang, Thomas L et al. (2005) Insensitivity to transforming growth factor-beta results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP). Mol Endocrinol 19:2390-9

Zhang, Qiang; Yang, Ximing; Pins, Michael et al. (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 65:1761-9

Ju, Eun Mi; Choi, Kyung-Chul; Hong, Seung-Hee et al. (2005) Apoptosis of mink lung epithelial cells by co-treatment of low-dose staurosporine and transforming growth factor-beta1 depends on the enhanced TGF-beta signaling and requires the decreased phosphorylation of PKB/Akt. Biochem Biophys Res Commun 328:1170-81