T. Matsuzaki et al., Induction of erythroid differentiation by inhibition of Ras/ERK pathway ina Friend murine leukemia cell line, ONCOGENE, 19(12), 2000, pp. 1500-1508
The role of Ras and MAP kinases (MAPKs) in the regulation of erythroid diff
erentiation was studied using a cell line (SKT6) derived from Friend virus
(Anemic strain)-induced murine erythroleukemia. This cell line undergoes di
fferentiation in vitro in response to erythropoietin (EPO) or other chemica
l inducers such as dimethylsulfoxide (DMSO), When a constitutively active r
as mutant (ras12V) was expressed in SKT6 cells, EPO-induced differentiation
was inhibited. Conversely, a dominant negative I au mutant (ras17N) induce
d differentiation even in the absence of EPO, suggesting that the basal Ras
activity is essential for the maintenance of the undifferentiated phenotyp
e and proliferative potential in this cell line. Rapid inactivation of ERK
was observed after expression of ras17N. Slow but significant inactivation
of ERR was also observed during EPO-induced differentiation. Furthermore, o
verexpression of a constitutively active mutant of ERK-activating kinase (M
APKK) was found to suppress erythroid differentiation, while pharmacologica
l inhibition of MAPKK induced differentiation. These findings suggest that
down-regulation of Ras/ERK signaling pathway may be an essential event in E
PO-induced erythroid differentiation in this system.