THE ROLE OF DIFFERENT KINASE PATHWAYS OF SIGNAL TRANSDUCTION IN PROLIFERATION OF E1A + Ras TRANSFORMANTS
M. V. Abramova,1 S. B. Svetlikova, V. V. Grinkevich, V. A. Pospelov
Institute of Cytology RAS, St. Petersburg, Russia;
1 e-mail: mav@mail.cytspb.rssi.ru
In this paper we have explored the role of different kinase pathways of signal transduction in proliferation
control of E1A + Ras transformants, using specific inhibitors of MAP-kinases ERK, JNK, p38 and PI3-kinase. According to our data,
suppression of signalling cascades driven by RI3K only arrested proliferation of E1A + Ras cells, while suppression of either
MAP-kinase did not lead to noticeable antiproliferative effect. We have shown that suppression of RI3K with LY294002 gave rise
to accumulation of cyclin-dependent kinase inhibitor ð27Kip1 but not p21Waf1. Accumulation of
ð27Kip1 in LY294002-treated E1A + Ras cells was accompanied by a decrease in Cyclin E-Cdk2 and Cyclin A-Cdk2 activity,
which caused diminution of Rb phosphorylation and strengthening of E2F-Rb binding. Binding of E2F with hypophosphorylated Rb
resulted in inhibition of E2F activity and reduction of E2F-regulated gene transcription, these genes being necessary for S-phase
entry and DNA synthesis. Thus, RI3K-Akt cascade plays the key role in maintenance of autonomous proliferation of cells transformed
with E1A and cHa-ras oncogenes. Inhibition of PI3K leads to p27Kip1 accumulation and cell cycle arrest, consequently.
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