Nedd9/Hef1/Cas-L Mediates the Effects of Environmental Pollutants on Cell Migration and Plasticity

Oncogene. 2009 Oct 15;28(41):3642-51. doi: 10.1038/onc.2009.224. Epub 2009 Aug 3.

Abstract

Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Dioxins / toxicity
  • Down-Regulation
  • Environmental Pollutants / toxicity*
  • Gene Knockdown Techniques
  • Humans
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Aryl Hydrocarbon / deficiency
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • Transcriptional Activation / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Dioxins
  • Environmental Pollutants
  • NEDD9 protein, human
  • Phosphoproteins
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon