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Tenascin-C blocks cell-cycle progression of anchorage-dependent fibroblasts on fibronectin through inhibition of syndecan-4

Oncogene volume 22, pages 3917–3926 (2003)Cite this article

Abstract

Tenascin-C is an adhesion-modulatory extracellular matrix protein that is predominantly expressed during embryonic development, wound healing and in tumor stroma. Here we report that anchorage-dependent human, rat and mouse fibroblasts adhere poorly and fail to proliferate on pure tenascin-C. This was due to a significant reduction of cyclin-dependent kinase 2 (cdk2) activity, resulting from elevated expression and association of the cdk inhibitors (CKIs) p21Cip1 and p27Kip1. To analyse the effect of tenascin-C on fibronectin-mediated adhesion, cells were plated on a mixed fibronectin/tenascin-C substratum. Compared to fibronectin alone, cell spreading and adhesion signaling were compromised, as determined by delayed phosphorylation kinetics of focal adhesion kinase (FAK). Despite the presence of growth factors, these cells remained arrested in the G1 phase of the cell cycle. In contrast to cells plated on pure tenascin-C, cdk2 activity appeared to be inhibited independently of CKIs. Interestingly, overexpression of the transmembrane proteoglycan syndecan-4 restored cell spreading, adhesion signaling and DNA replication on the fibronectin/tenascin-C substratum. A similar rescue was observed using a recombinant peptide that spans the syndecan-4-binding site in fibronectin. This indicates that tenascin-C causes cell cycle arrest and cdk2 inactivation by interfering with fibronectin–syndecan-4 interactions. We therefore propose that syndecan-4 signaling plays a central role in the control of cellular proliferation of anchorage-dependent fibroblasts.

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Abbreviations

FCS:

fetal calf serum

HDF:

human diploid fibroblast

Cdk:

cyclin-dependent kinase

ECM:

extracellular matrix

EILPT:

growth factor cocktail (EGF, insulin, LPA, PBGF-BB, TGFβ)

CKI:

cyclin-dependent kinase inhibitor

FAK:

focal adhesion kinase

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Acknowledgements

We thank Hartmut Beug for the HDF fibroblasts, Tony Hunter for the cyclin A antibody, Richard Hynes for FNIII13, Anne Woods and Guido David for syndecan-4 cDNA and antibodies and Ulrich Müller for the β1 integrin antibody. We also thank Josephine A Adams for discussion and critical comments on the manuscript and Erika Fluri for technical assistance. GO was supported by long-term fellowships from EMBO and The Swiss Cancer League (Gertrud Hagmann Stiftung für Malignomforschung).

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  1. Gertraud Orend & Wentao Huang

    Present address: Institute of Biochemistry and Genetics, University Basel, Vesalgasse 1, 4051, Basel, Switzerland

  2. Monilola A Olayioye

    Present address: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Victoria, 3052, Australia

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Novartis Forschungsstiftung, PO Box 2543, Basel, CH-4002, Switzerland

    Gertraud Orend, Wentao Huang, Monilola A Olayioye, Nancy E Hynes & Ruth Chiquet-Ehrismann

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Correspondence to Gertraud Orend.

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Orend, G., Huang, W., Olayioye, M. et al. Tenascin-C blocks cell-cycle progression of anchorage-dependent fibroblasts on fibronectin through inhibition of syndecan-4. Oncogene 22, 3917–3926 (2003). https://doi.org/10.1038/sj.onc.1206618

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