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Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

Oncogene volume 22, pages 412–425 (2003)Cite this article

Abstract

NF-κB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-κB activity by TGF-β1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-κB is transiently activated in response to TGF-β1 treatment. Here we elucidate the mechanism of TGF-β1-mediated regulation of NF-κB and induction of apoptosis in epithelial cells. We report that TGF-β1 activates IKK kinase, which mediates IκB-α phosphorylation. In turn, the activation of IKK following TGF-β1 treatment is mediated by the TAK1 kinase. As a result of NF-κB activation, IκB-α mRNA and protein levels are increased leading to postrepression of NF-κB and induction of cell death. Inhibition of NF-κB following TGF-β1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-β1-mediated upregulation of Smad7 appeared independent of NF-κB. In hepatocellular carcinomas of TGF-β1 or TGF-α/c-myc transgenic mice, we observed constitutive activation of NF-κB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-κB/IκB-α signaling to negatively regulate NF-κB levels thereby permitting TGF-β1-induced apoptosis through AP-1 activity.

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Acknowledgements

We gratefully acknowledge John Hiscott, Nelson Fausto, Qimin Zhan, Yasuko Yamamura, Carlos Paya, David Sassoon, Hiroaki Sakurai, Parker Suttle, Kyoko Yamaguchi, Michael Karin, Robert Korneluk, and Peter ten Dijke for kindly providing cloned DNAs and cell lines.

This work was supported by grants from the Charlotte Geyer Foundation (MA), from the ACS IRG-72-001-24 (MA) and CA78616 (MA) and in part from the NIH Grants CA82742 and CA36355 (G.E.S.). GR Panta was sponsored in part by the American Liver Foundation Irwin M Arias, MD, Postdoctoral Research Fellowship. JD Bilyeu was sponsored by a predoctoral fellowship from the NIHPhRMA Foundation. LG Cavin was supported by a Research Supplement for Under Represented Minorities Program CA78616-S1.

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Authors and Affiliations

  1. Department of Pharmacology, University of Tennessee College of Medicine, Memphis, 38163, TN, USA

    Marcello Arsura, Ganesh R Panta, Jennifer D Bilyeu & Lakita G Cavin

  2. Department of Biochemistry, Boston University School of Medicine, Boston, 02118-2394, MA, USA

    Mika A Sovak, Aundrea A Oliver & Gail E Sonenshein

  3. Laboratory of Experimental Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute, Bethesda, 20892, MD, USA

    Valentina Factor & Snorri S Thorgeirsson

  4. Ludwig Institute for Cancer Research, Uppsala, S-751 24, Sweden

    Rainer Heuchel

  5. Celgene Signal Research Division, San Diego, 92121, CA, USA

    Frank Mercurio

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Arsura, M., Panta, G., Bilyeu, J. et al. Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22, 412–425 (2003). https://doi.org/10.1038/sj.onc.1206132

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