Disruption of c-Jun reduces cellular migration and invasion through inhibition of c-Src and hyperactivation of ROCK II kinase

Mol Biol Cell. 2008 Apr;19(4):1378-90. doi: 10.1091/mbc.e07-08-0753. Epub 2008 Jan 23.

Abstract

The spread of metastatic tumors to different organs is associated with poor prognosis. The metastatic process requires migration and cellular invasion. The protooncogene c-jun encodes the founding member of the activator protein-1 family and is required for cellular proliferation and DNA synthesis in response to oncogenic signals and plays an essential role in chemical carcinogenesis. The role of c-Jun in cellular invasion remains to be defined. Genetic deletion of c-Jun in transgenic mice is embryonic lethal; therefore, transgenic mice encoding a c-Jun gene flanked by LoxP sites (c-jun(f/f)) were used. c-jun gene deletion reduced c-Src expression, hyperactivated ROCK II signaling, and reduced cellular polarity, migration, and invasiveness. c-Jun increased c-Src mRNA abundance and c-Src promoter activity involving an AP-1 site in the c-Src promoter. Transduction of c-jun(-/-) cells with either c-Jun or c-Src retroviral expression systems restored the defective cellular migration of c-jun(-/-) cells. As c-Src is a critical component of pathways regulating proliferation, survival, and metastasis, the induction of c-Src abundance, by c-Jun, provides a novel mechanism of cooperative signaling in cellular invasion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Actins / metabolism
  • Animals
  • Cell Movement / genetics*
  • Cell Movement / physiology*
  • Cells, Cultured
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Female
  • Focal Adhesions / genetics
  • Focal Adhesions / physiology
  • Gene Deletion
  • Genes, jun*
  • Genes, src*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism
  • Mice
  • Mice, Transgenic
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / physiopathology
  • Paxillin / chemistry
  • Paxillin / metabolism
  • Phosphorylation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism*

Substances

  • Actins
  • Paxillin
  • Pxn protein, mouse
  • RNA, Messenger
  • rho-Associated Kinases