Journal
ONCOGENE
Volume 26, Issue 8, Pages 1222-1230Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209902
Keywords
TJ; occluding; Slug; Raf 1
Funding
- Intramural NIH HHS Funding Source: Medline
- NIDDK NIH HHS [DK 61379, DK 59888] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008169] Funding Source: Medline
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Although dysregulation of tight junction (TJ) proteins is observed in epithelial malignancy, their participation in epithelial transformation is poorly understood. Recently we demonstrated that expression of oncogenic Raf 1 in Pa4 epithelial cells disrupts TJs and induces an oncogenic phenotype by downregulating expression of the TJ protein, occludin. Here we report the mechanism by which Raf 1 regulates occludin expression. Raf 1 inhibited occludin transcription by repressing a minimal segment of the occludin promoter in concert with upregulation of the transcriptional repressor, Slug without influencing the well-documented transcriptional repressor, Snail. Overexpression of Slug in Pa4 cells recapitulated the effect of Raf 1 on occludin expression, and depletion of Slug by small interfering RNA abrogated the effect of Raf 1 on occludin. Finally, chromatin immunoprecipitation assays and site- directed mutagenesis demonstrated a direct interaction between Slug and an E-box within the minimal Raf 1-responsive segment of the occludin promoter. These findings support a role of Slug in mediating Raf 1-induced transcriptional repression of occludin and subsequent epithelial to mesenchymal transition.
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