Opposite long-term regulation of @entity517 and @entity13525 through overactivation of @entity10242 and the @entity8047 / @entity3963 module in proliferating XXXX @entity320 cells.

@entity1 @entity8047 @entity5 @entity3963 @entity517 @entity10242 @entity13525 @entity27521 @entity320
Although there is no current evidence for ras gene mutation in @entity320 , there is an increasing body of evidence indicating that deregulated intracellular signalling pathways are involved in @entity320 pathogenesis. The various components of the linear Raf/ @entity8047 / @entity3963 signalling pathway have been implicated in various @entity5 . We therefore investigated the role of @entity10242 and the @entity8047 / @entity3963 module in the proliferation of @entity1 normal choroidal melanocytes (NCM) and cells from the ocular @entity320 ( @entity27521 ) cell line. @entity27521 cells proliferated four times faster than NCM. High basal activation of the @entity8047 / @entity3963 module was observed in unstimulated @entity27521 cells, whereas rapid and persistent activation was detected after serum stimulation, throughout the 24-h period of culture. In contrast, the activation of @entity8047 / @entity3963 was barely detectable in unstimulated NCM and occurred late (6 h) after the stimulation of cell proliferation. Inhibition of @entity10242 and MEK1/2 activation by pharmacological approaches and of the production of @entity10242 and ERK1/2 by antisense oligonucleotide approaches demonstrated that @entity10242 and the @entity8047 / @entity3963 module controlled proliferation in @entity27521 cells, but not in NCM. @entity27521 cells produced very low levels of @entity13525 , whereas NCM produced constant, high levels of @entity13525 . The inhibition of @entity10242 or MEK1/2 induced a large increase in @entity13525 in @entity27521 cells, associated with an arrest of cell proliferation. Levels of @entity517 production were high and constant in @entity27521 cells and low in NCM, in contrast to what was observed for @entity13525 . The inhibition of both @entity10242 and MEK1/2 induced a decrease in @entity517 production and downregulated @entity517 activity by preventing @entity517 phosphorylation in @entity27521 cells. We conclude that @entity10242 and the @entity8047 / @entity3963 module control the production of both @entity13525 and @entity517 , and the activation of @entity517 for @entity27521 cell proliferation.
