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Vol. 8, Issue 11, 2329-2344, November 1997
Department of Cell Biology and Anatomy, University of North
Carolina at Chapel Hill, North Carolina 27599-7090
Oncogenic transformation of cells alters their morphology,
cytoskeletal organization, and adhesive interactions. When the mammary
epithelial cell line MCF10A is transformed by activated H-Ras, the
cells display a mesenchymal/fibroblastic morphology with decreased
cell-cell junctions but increased focal adhesions and stress fibers.
We have investigated whether the transformed phenotype is due to Rho
activation. The Ras-transformed MCF10A cells have elevated levels of
myosin light chain phosphorylation and are more contractile than their
normal counterparts, consistent with the activation of Rho.
Furthermore, inhibitors of contractility restore a more normal
epithelial phenotype to the Ras-transformed MCF10A cells. However,
inhibiting Rho by microinjection of C3 exotransferase or dominant
negative RhoA only partially restores the normal phenotype, in that it
fails to restore normal junctional organization. This result prompted
us to examine the effect that inhibiting Rho would have on the
junctions of normal MCF10A cells. We have found that inhibiting Rho by
C3 microinjection leads to a disruption of E-cadherin cytoskeletal
links in adherens junctions and blocks the assembly of new adherens
junctions. The introduction of constitutively active Rho into normal
MCF10A cells did not mimic the Ras-transformed phenotype. Thus, these
results lead us to conclude that some, but not all, characteristics of
Ras-transformed epithelial cells are due to activated Rho. Whereas Rho
is needed for the assembly of adherens junctions, high levels of
activated Rho in Ras-transformed cells contribute to their altered
cytoskeletal organization. However, additional events triggered by Ras
must also be required for the disruption of adherens junctions and the
full development of the transformed epithelial phenotype.
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