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TGFβ influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b

Nature Cell Biology volume 3, pages 400–408 (2001)Cite this article

Abstract

Transforming growth factor-β (TGFβ) is a cytokine that arrests epithelial cell division by switching off the proto-oncogene c-myc and rapidly switching on cyclin-dependent kinase (CDK) inhibitors such as p15INK4b. Gene responses to TGFβ involve Smad transcription factors that are directly activated by the TGFβ receptor. Why downregulation of c-myc expression by TGFβ is required for rapid activation of p15INK4b has remained unknown. Here we provide evidence that TGFβ signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFβ-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. Thus, two separate TGFβ-dependent inputs — Smad-mediated transactivation and relief of repression by Myc — keep tight control over p15INK4b activation.

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Figure 1: The p15 Inr is a TGFβ response element.
Figure 2: TGFβ reduces levels of an endogenous Myc–Miz-1 complex that binds to the p15 Inr.
Figure 3: Miz-dZF interferes with recruitment of Myc to DNA.
Figure 4: Effect of Miz-dZF on the endogenous p15INK4b response to TGFβ.
Figure 5: Characterization of a Smad-binding region in the p15INK4b promoter.
Figure 6: Myc represses Smad-responsive enhancers.
Figure 7: Interaction of Smad and Miz-1.
Figure 8: Two-input model of TGFβ-mediated induction of p15INK4b.

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Acknowledgements

We thank F. Liu for Smad7 promoter constructs, and A. Hata, Y. Chen, R. Lo and D. Wotton for discussions. J.S. is a Fellow of the Ministerio de Educación y Cultura of Spain. C.P. and J.M. are, respectively, a Research associate and an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue , New York, 10021, New York, USA

    Joan Seoane, Celio Pouponnot & Joan Massagué

  2. Institute of Molecular Biology and Tumour Research , Emil Mankoff Strasse 2, Marburg , 35033, Germany

    Peter Staller, Manuela Schader & Martin Eilers

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Correspondence to Joan Massagué.

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Figure S1

Promoter analysis of p15Ink4b. (PDF 22 kb)

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Seoane, J., Pouponnot, C., Staller, P. et al. TGFβ influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol 3, 400–408 (2001). https://doi.org/10.1038/35070086

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