H. Rus et al., TERMINAL COMPLEMENT COMPLEXES INDUCE CELL-CYCLE ENTRY IN OLIGODENDROCYTES THROUGH MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY, Immunopharmacology, 38(1-2), 1997, pp. 177-187
Sublytic complement attack through C5b-9 assembly induces oligodendroc
ytes (OLG) to express proto-oncogenes and to enter the cell cycle from
resting G0/G1 phase to S phase. We have investigated whether cell cyc
le induction by C5b-9 is mediated by mitogen activated protein kinase
(MAPK) pathway in OLG. C5b-9 but not C5b6 induced activation of both E
RK1 and c-jun NH2 terminal kinases 1 (JNK1) in OLG. The increased ERK1
and JNK1 activities are transient, reaching a maximum around 20 min f
ollowing exposure to C5b-9, Activation of Raf-l and MEK1, upstream kin
ases of ERK1, was shown by increased Raf-l kinase activity in anti-Raf
-l immunoprecipitates of OLG treated with C5b-9 and ERK1 activity that
can be inhibited by PD098,059, a specific MEK1 inhibitor. Requirement
for the ERK1 pathway in DNA synthesis was then evaluated using PD098,
059. Enhanced DNA synthesis induced by serum complement was completely
abolished when OLG were pretreated with PD098,059. On the other hand,
c-fos mRNA expression induced by complement was inhibited only 50% by
PD098,059, while the c-jun mRNA level was not affected by this MEK1 i
nhibitor. Interestingly, p70 S6 kinase, an important ribosomal kinase
in mitogenesis, was also activated by C5b-9. These findings indicated
that the MAPK pathways appears to play a major role in inducing OLG to
enter the S phase of the cell cycle from the resting G1/G0 phase. (C)
1997 Elsevier Science B.V.