科研之友
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摘要
Epithelial-mesenchymal transformation (EMT) in response to TGF beta I is a coordinated process of tissue morphogenesis that occurs during embryonic development as well as during certain pathologic events including kidney tubulointerstitial fibrosis. It is characterized by the disassembly of cell-cell junctions and dramatic alterations in the actin cytoskeleton that facilitates cell-matrix adhesion and stimulates migration. The focal adhesion adapter protein, Hic-5, has previously been reported to be upregulated during TGF beta I-induced EMT in mouse mammary epithelial cells and the current study recapitulates this result in both mouse kidney proximal tubule epithelial, MCT, cells and human mammary epithelial, MCF10A, cells. To evaluate a causative role for Hic-5 in EMT, Hic-5 RNA interference (siRNA) was used to prevent Hic-5 expression in response to TGF beta I stimulation and was shown to suppress cell migration and actin stress fiber formation. It also resulted in the retention of a robust epithelial cell morphology characterized by elevated E-cadherin protein expression and well-organized adherens junctions. In addition, Hic-5 siRNA treatment led to the suppression of TGF beta I induction of RhoA activation. In contrast, forced expression of Hic-5 led to the formation of ROCK-dependent actin stress fibers. Furthermore, the induction of Hic-5 expression in response to TGF beta I was shown to be a RhoA/ROCKI-dependent process. Together, these data implicate Hic-5 as a key regulator of EMT and suggest that RhoA stimulated Hic-5 expression in response to TGF beta I may be functioning in a feed forward mechanism whereby Hic-S maintains the mesenchymal phenotype through sustained RhoA activation and signaling.
- 出版日期2007-6
