JNK- And Fos-regulated Mmp1 Expression Cooperates With Ras to Induce Invasive Tumors in Drosophila

EMBO J. 2006 Nov 15;25(22):5294-304. doi: 10.1038/sj.emboj.7601401. Epub 2006 Nov 2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Movement
  • Cell Polarity
  • Cell Proliferation
  • Cell Survival
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / physiology*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Matrix Metalloproteinase 1 / biosynthesis
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Models, Biological
  • Mutation
  • Neoplasm Invasiveness*
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinases / physiology
  • ras Proteins / physiology*

Substances

  • Drosophila Proteins
  • Membrane Proteins
  • Scrib protein, Drosophila
  • Tissue Inhibitor of Metalloproteinases
  • kay protein, Drosophila
  • JNK Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 1
  • ras Proteins