A protein kinase C-independent pathway leading to c-Jun-dependent expression of 100-kDa Ras GTPase-activating protein in JEG-3 human choriocarcinoma cells
F. Ye et al., A protein kinase C-independent pathway leading to c-Jun-dependent expression of 100-kDa Ras GTPase-activating protein in JEG-3 human choriocarcinoma cells, EUR J BIOCH, 267(6), 2000, pp. 1589-1597
Although the 100-kDa Ras GTPase-activating protein (p100 RasGAP) has been r
eported to exist specifically in human placental trophoblasts, the molecula
r mechanisms responsible for regulating its expression remain unclear. In t
his study we used okadaic acid, an inhibitor of serine/threonine phosphatas
e 1 and 2 A, as a probe to explore the signaling pathway regulating the exp
ression of p100 RasGAP in JEG-3 human placental choriocarcinoma cells. Trea
tment of JEG-3 cells with okadaic acid provoked dose- and time-dependent st
imulation of p100 RasGAP expression without marked modification of expressi
on of p120 RasGAP, another isoform of RasGAP. Co-treatment of cells with ok
adaic acid and the protein kinase C activator, phorbol 12-myristate 13-acet
ate, exerted an additive effect on p100 RasGAP induction. Moreover, the res
ponse of the p100 RasGAP de novo synthesis to okadaic acid was not affected
by the selective inhibitor of protein kinase C, GF 109203X. Thus this stud
y identified a novel signaling pathway regulating p100 RasGAP expression, w
hich is independent of protein kinase C. In addition, okadaic acid treatmen
t resulted in the activation of ERK2 (p42 MAP kinase) and the induction of
both c-Jun and c-Fos proteins without activating JNK (c-Jun NH2-terminal ki
nase). Significantly, blockade of c-Jun expression with antisense c-jun oli
gonucleotides suppressed p100 RasGAP expression. Taken together, it is conc
luded that okadaic acid induces the expression of p100 RasGAP protein in JE
G-3 cells preceded by activation of ERK and AP-1 cascade, and that this oka
daic acid-induced p100 RasGAP expression is independent of protein kinase C
-mediated pathway but requires c-Jun/AP-1 function.