Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2.
Overexpression of the forkhead family transcription factor Foxc2 has been shown to activate epithelial-mesenchymal transition (EMT) and correlate with tumor metastasis. In this study, we show that both mRNA and protein levels of Foxc2 increase 1 day after kidney ischemia/reperfusion in sublethally injured tubular cells and that the protein is located in the cytoplasm rather than the nucleus of these cells. in vitro studies of cultured tubular cells confirm the cytoplasmic location of Foxc2 and show that increased cytoplasmic expression of Foxc2 correlates with epithelial differentiation rather than dedifferentiation. Silencing of Foxc2 by RNAi in these cells led to EMT and increased cell migration. In contrast, Foxc2 is found in both the nucleus and cytoplasm of cultured fibroblasts, with RNAi leading to increased expression of epithelial markers and impaired cell migration. Consistent with a subcellular localization dependence of Foxc2 function, overexpression of Foxc2 in renal epithelial cells resulted in de novo nuclear expression of the protein and promotion of a mesenchymal/fibroblast phenotype. These results suggest that Foxc2 may have regulatory functions independent of its nuclear transcriptional activity and that upregulation of endogenous Foxc2 in the cytoplasm of injured tubular cells activates epithelial cell redifferentiation rather than dedifferentiation during organ repair.
Hader
C
C
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Marlier
A
A
Cantley
L
L
D000818:Animals; D054337:Cell Dedifferentiation; D002467:Cell Nucleus / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D021381:Protein Transport; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation; D014945:Wound Healing
D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein