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| Subject Categories: Signal Transduction | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 5294–5304, doi:10.1038/sj.emboj.7601401 Published online 2 November 2006 |
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| JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila |
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| Mirka Uhlirova and Dirk Bohmann |
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Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA To whom correspondence should be addressed Dirk Bohmann, Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue Box 633, Rochester, NY 14642, USA. Tel.: +1 585 273 1446; Fax: +1 585 273 1450; E-mail: Dirk_Bohmann@urmc.rochester.edu Received 8 February 2006; Accepted 26 September 2006; Published online 2 November 2006. |
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| Abstract |
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| Loss of the epithelial polarity gene scribble in clones of Drosophila imaginal disc cells can cooperate with Ras signaling to induce malignant tumors. Such mutant tissue overproliferates, resists apoptosis, leaves its place of origin and invades other organs, ultimately causing lethality. We show that increased Jun N-terminal kinase (JNK) signaling resulting from the loss of scribble promotes the movement of transformed cells to secondary sites. This effect requires Fos-dependent transcriptional activation of a matrix metalloprotease gene mmp1 downstream of JNK. Expression of the Mmp inhibitor Timp or Mmp RNAi knockdown suppresses cell invasiveness. The proinvasive function of the JNK pathway is revealed in a tumor context when active Ras signaling prevents the apoptotic response to JNK activity as it occurs in nontransformed cells. Based on these results, we present a model that explains the oncogenic cooperation between JNK and Ras, and describes how aberrant regulation of cell survival, proliferation and mobilization cooperate to incite malignant tumor formation. |
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| Keywords: Fos, JNK, Mmp, oncogene cooperation, Ras |
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