Isolation of Transcription Factor Involved in Expression of Tgfb II Receptor

Kim, S J.

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 responsaiveness 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. We have studied several TGF-beta resistant cell lines in which Southern analysis failed to show gross deletions or rearrangements, yet in which no TGF-beta RII protein or mRNA was produced. This suggested that abnormalities in transcriptional regulation of the RII might also be found to underlie certain instances of escape from TGF-beta mediated growth inhibition. In order to identify potential transcriptional activators of the TGF- beta RII gene, we adapted the yeast one-hybrid system to find proteins that recognize the second positive regulatory element of the TGF-beta RII gene. We isolated a 2.5-kb cDNA clone that encodes a 371 amino acid novel transcription factor from a human placenta cDNA library which belongs to a novel member of the ets transcription factor family. Using constructs of the TGF-beta RII promoter linked to the luciferase gene, we have demonstrated that this transcription factor, ERT, activates transcription of the TGF-beta RII gene. A specific interaction between ERT and the TGF-beta promoter element was also demonstrated using an electrophoretic mobility shift assay. We also demonstrated that there is a good correlation between expression patterns of TGF-beta RII mRNA and ERT mRNA in human gastric cancer cell lines. Our results suggest that ERT might be a major transcription factor involved in the transcriptional regulation of the TGF-beta RII gene.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Intramural Research (Z01)
• Project #: 1Z01BC005617-09
• Application #: 6160933
• Study Section: Special Emphasis Panel (LC)
• Support Year: 9
• Fiscal Year: 1997

Institution

• Name: National Cancer Institute Division of 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

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