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Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors

Oncogene volume 19, pages 640–648 (2000)Cite this article

Abstract

Hepatocyte growth-factor (HGF) is a potent, widely produced, pleiotropic mediator of mesenchymal-epithelial interaction. In a study of changes in gene expression initiated by HGF in Balb/MK keratinocytes, we observed the induction of Neu-differentiation factor (NDF) mRNA (also known as heregulin, or HRG). Further characterization of the regulation of NDF expression in Balb/MK keratinocytes revealed potent induction by keratinocyte growth factor (KGF) and epidermal growth factor (EGF), but not by HGF/NK2, an alternative HGF isoform with motogenic but not mitogenic or morphogenic activities. Sustained treatment (8 h) of Balb/MK cells with KGF stimulated secretion of mature NDF protein into the culture medium, and Balb/MK cells treated with purified recombinant NDF protein showed increased DNA synthesis. We also found evidence of NDF induction in two models of tissue repair in mice: in full-thickness skin wounds, following locally increased KGF production, and in kidney after partial hepatectomy, following elevation of circulating HGF levels. These results reveal that mesenchymally-derived HGF and KGF can activate autocrine NDF signaling in their epithelial targets, and suggest that this mechanism contributes to the coordination of stages of wound repair, and possibly development, where these growth factors act in concert to direct epithelial proliferation, morphogenesis and differentiation.

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Acknowledgements

We thank Drs J Rubin and LM Wang for helpful discussions.

Author information

Author notes

  1. Paola Castagnino

    Present address: Dept. of Pharmacology, University of Pennsylvania, Philadelphia, 19104-6084, PA, USA

  2. Matthew V Lorenzi

    Present address: Target Discovery Department, Zeneca Pharmaceuticals, PO Box 15437, 1800 Concord Pike, Wilmington, Delaware, USA

  3. Hiromi Sakata

    Present address: Second Department of Surgery, Asahikawa Medical College, Nishi-Kagura 4-5, Asahikawa, 078, Hokkaido, Japan

  4. Barbara Munz

    Present address: Department of Biochemistry and Molecular Pharmacology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, 94305-5332, California, CA, USA

  5. Sabine Werner

    Present address: Institute of Cell Biology, ETH-Honggerberg, Zurich, CH-8093, Switzerland

Authors and Affiliations

  1. Division of Basic Sciences, Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

    Paola Castagnino, Matthew V Lorenzi, Juddi Yeh, Diane Breckenridge, Hiromi Sakata & Donald P Bottaro

  2. Max Plank Institute for Biochemistry, Martinsried, Germany

    Barbara Munz & Sabine Werner

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Castagnino, P., Lorenzi, M., Yeh, J. et al. Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors. Oncogene 19, 640–648 (2000). https://doi.org/10.1038/sj.onc.1203357

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