CHANGES IN THE ACTIVITY OF CYCLIN-Cdk COMPLEXES GOVERNING G1/S
TRANSITION IN ElA+c-Ha-ras-TRANSFORMANTS TRANSFECTED WITH bcl-2 GENE
A. M. Nelyudova,1 N. D. Aksenov, T. V. Pospelova
Institute of Cytology RAS, St. Petersburg;
1 e-mail: start@histo.bio.pu.ru
The antiproliferative effect of human bcl-2 gene transferred to ElA+c-Ha-ras-transformed rat embryo
fibroblasts, which are characterized by the absence of cell cycle checkpoints after damage and by a high proapoptotic
sensitivity was studied. Ionizing irradiation, adriamycin treatment, and serum starvation were shown to induce
G1/S arrest in ElA+c-Ha-ras-transformants. Bcl-2 antiproliferative effect in
ElA+c-Ha-ras-transformants was not associated with alteretions in Cdk2, cyclin E and A contents. G1/S
arrest following irradiation or serum starvation was accompanied by a decrease in kinase activity associated with
cyclin E-cdk2, whereas G1/S arrest in tetraploid subpopulation after adriamycin treatment did not
correlate with a decrease in cyclin E-associated kinase activity. Cyclin A-associated kinase activity did not
decrease after any used treatment. Transfection of bcl-2 in El A+c-Ha-ras-transformants resulted in elevated
expression of cyclin-cdk complexes inhibitor p21/Waf-l, but not p27/Kip. Damaging agents caused p21/Waf-l and
p27/Kip accumulation, but bcl-2 overexpression did not restore functions of these inhibitors, since
p21/Waf-l and p27/Kip were unable to suppress cyclin-cdk complexes activity after damage. These results suggest
that bcl-2 transfection in ElA+c-Ha-ras-transformants is likely to result in irradiation- or serum
starvation-induced G1/S arrest accomplished by a selective decrease in cyclin E-associated kinase
activity. Adriamycin-induced G1/S arrest seems to be realized via cyclin-cdk complexes
activity-independent way involving antiproliferative targets downstrem of cyclin E-cdk2 and cyclin A-cdk2
complexes.
Key words: cell cycle, G1/S arrest, human bcl-2 gene E1A, c-Ha-ras
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