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c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1

Oncogene volume 20, pages 3443–3448 (2001)Cite this article

Abstract

Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis that acts directly on endothelial cells via the CD36 surface receptor molecule to halt their migration, proliferation, and morphogenesis in vitro and to block neovascularization in vivo. Here we show that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK). Rather, TSP-1 induced a rapid and transient activation of c-Jun N-terminal kinases (JNK). JNK activation by TSP-1 required engagement of CD36, as it was blocked by antagonistic CD36 antibodies and stimulated by short anti-angiogenic peptides derived from TSP-1 that act exclusively via CD36. TSP-1 inhibition of corneal neovascularization induced by bFGF was severely impaired in mice null for JNK-1, pointing to a critical role for this stress-activated kinase in the inhibition of neovascularization by TSP-1.

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Acknowledgements

This work was funded by NIH grants CA52750 and CA64239 to N Bouck and by American Heart Association grant AHA SGD 0030023N to OV Volbert and by Plan Nacional de I+D grant SAF 98-0060 to A Muñoz and Comunidad de Madrid 08.1/0010/2000 to B Jiménez. L Chang was supported by a fellowship from Bank of America-Ginnini Foundation. M Karin is the Frank and Else Schilling American Cancer Society Research Professor.

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Authors and Affiliations

  1. Department of Microbiology-Immunology and Robert H Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA

    Olga V Volpert, Frank Reiher & Noël Bouck

  2. Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain

    Benilde Jiménez

  3. Instituto de Investigaciones Biomédicas, “Alberto Sols” Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Madrid, Spain

    Benilde Jiménez & Alberto Muñoz

  4. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego, La Jolla, California, USA

    Lufen Chang & Michael Karin

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  1. Benilde Jiménez
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Jiménez, B., Volpert, O., Reiher, F. et al. c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1. Oncogene 20, 3443–3448 (2001). https://doi.org/10.1038/sj.onc.1204464

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