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Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73

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Abstract

RECENT advances indicate a link between tumour promoters, transformation, and AP-1 activity1. Protein kinase C activation increases AP-1 DNA-binding activity independently of new protein synthesis2,3. AP-1 is also stimulated by transforming oncoproteins and growth factors4–6. These proteins are thought to participate in a signalling cascade affecting the nuclear AP-1 complex composed of the Jun and Fos proteins1,7,8. Because c-Jun is the most potent transactivator in the AP-1 complex9–12 and is elevated in Ha-ras-transformed cells, in which c-Fos is downregulated13,14, we focused on it as a potential target. c-Jun could convert input from an oncogenic signalling cascade into changes in gene expression. Indeed, transformation of rat embryo fibroblasts by c-Jun requires an intact transcriptional activation domain15 and cooperation with oncogenic Ha-ras16. Expression of oncogenic Ha-ras augments transactivation by c-Jun and stimulates its phosphorylation14. Here we describe the mapping of the Ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-Jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-Jun activity and for cooperation with Ha-ras in ocogenic transformation.

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Author notes

  1. Bernard Binetruy

    Present address: Institut Curie, Biologie, Centre Universitaire, Orsay, 91405, France

  2. Michael Karin: To whom correspondence should be addressed.

Authors and Affiliations

  1. Department of Pharmacology, Center for Molecular Genetics, University of California San Diego, School of Medicine, La Jolla, California, 92093-0636, USA

    Tod Smeal, Bernard Binetruy & Michael Karin

  2. Department of Biology, Center for Molecular Genetics, University of California San Diego, School of Medicine, La Jolla, California, 92093-0636, USA

    Tod Smeal

  3. Department of Pathology, Center for Molecular Genetics, University of California San Diego, School of Medicine, La Jolla, California, 92093-0636, USA

    Daniel A. Mercola

  4. Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland, 20814, USA

    Michael Birrer

Authors
  1. Tod Smeal
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  2. Bernard Binetruy
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  3. Daniel A. Mercola
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  4. Michael Birrer
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  5. Michael Karin
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Smeal, T., Binetruy, B., Mercola, D. et al. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354, 494–496 (1991). https://doi.org/10.1038/354494a0

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  • DOI: https://doi.org/10.1038/354494a0

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