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TGFβ inducible early gene enhances TGFβ/Smad-dependent transcriptional responses

Oncogene volume 21, pages 5783–5790 (2002)Cite this article

Abstract

TGFβ inducible early gene (TIEG) encodes a three zinc-finger Krüppel-like transcription factor whose overexpression has been shown to mimic the effects of TGFβ in human osteosarcoma and pancreatic carcinoma cells. In order to investigate a potential role of TIEG in the TGFβ signal transduction pathway, we studied its impact on a Smad binding element (SBE) reporter which is known to be regulated by TGFβ through the R-Smad proteins. We demonstrate that TIEG overexpression enhances TGFβ induction of SBE reporter activity. TIEG overexpression also enhances induction of the endogenous TGFβ regulated genes p21 and PAI-1. The ability of TIEG to enhance TGFβ actions is Smad dependent since TIEG has no effect on SBE transcription in the absence of Smad4 expression or when an inhibitory Smad protein, Smad7, is overexpressed. Furthermore, TIEG overexpression enhances TGFβ induced Smad2 phosphorylation. Lastly, TIEG appears to function by binding to and thereby repressing a specific element in the proximal promoter of the inhibitory Smad7 gene. In conclusion, these results describe a novel mechanism for the potentiation of TGFβ/Smad signaling via repression of the inhibitory Smad7 gene by TIEG.

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Acknowledgements

We thank the following for graciously providing plasmids: Dr M Kato and K Miyazono (ALK5TD expression construct), P ten Dijke (mSmad7 expression construct), E Böttinger (human Smad7 promoter), Y Chen (mouse Smad7 promoter), and A Rustgi (cyclin D1 promoter). We would like to thank K Rasmussen and T Ruesink for their outstanding technical support. SA Johnsen was supported by a predoctoral fellowship from the Mayo Foundation. R Janknecht was supported by a scholarship from the Sidney Kimmel Foundation for Cancer Research. This work was supported by the NIH grant 1RO1 DE14036-01A1, the Mayo Foundation, and the Mazza Foundation.

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  1. Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, 55905, Minnesota, MN, USA

    Steven A Johnsen, Malayannan Subramaniam, Ralf Janknecht & Thomas C Spelsberg

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  1. Steven A Johnsen
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  2. Malayannan Subramaniam
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  3. Ralf Janknecht
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  4. Thomas C Spelsberg
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Correspondence to Thomas C Spelsberg.

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Johnsen, S., Subramaniam, M., Janknecht, R. et al. TGFβ inducible early gene enhances TGFβ/Smad-dependent transcriptional responses. Oncogene 21, 5783–5790 (2002). https://doi.org/10.1038/sj.onc.1205681

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