E1A ONCOGENE EFFECT ON THE ABILITY OF p21Waf1 TO REGULATE G1/S ARREST IN
E1A-EXPRESSING TRANSFORMANTS FOLLOWING IRRADIATION
V. S. Romanov,1 A. I. Brichkina, V. A. Pospelov, T. V. Pospelova
Institute of Cytology RAS, St. Petersburg, Russia;
1 e-mail: vsromanov@hotmail.com
p21Waf1 cyclin-dependent kinase inhibitor blocks cell cycle transition from G1 phase into
DNA replication after DNA damage. The main targets of p21Waf1 are CyclE-Cdk2 and CyclA-Cdk2 complexes, PCNA
(proliferating cell nuclear antigen), a subunit of DNA polymerase δ, and E2F-1 transcription factor. The universal
mechanism of cell cycle arrest in normal cells is determined as p21Waf1 interaction with positive regulators of
G1 phase. As a rule, DNA integrity control mechanisms are destroyed in the process of oncogenic transformation, which
results in proliferation of genetically defective cells. The purpose of our study was to investigate molecular mechanisms of cell
cycle regulation in transformants that are able (E1A + E1B-19kDa) or unable (E1A + + cHa-ras) to be arrested at G1/S checkpoint.
We have shown that p21Waf1 is able to form complexes with cyclins and Cdks, PCNA and E2F-1 transcryption factor,
although it interacts with E1A oncoproducts in both transformants. The presence of E1A bound p21Waf1 in cyclin-kinase
complexes seems to be the cause of activating phosphorilation of Cdk2 at Thr-160 in cyclin A/E-Cdk2 complexes in both control and
X-ray irradiated cells. Thus, the absence of G1/S arrest following irradiation in E1A + cHa-ras transformants and its
presence in E1A + E1B-19kDa transformants is not connected with differences in interaction of p21Waf1 with the main regulators of
G1-to-S transition, but is realized through other not yet identified ways.
Key words: E1A, E1B-19kDa and cHa-ras oncogenes, G1/S arrest of the cell cycle,
p21Waf1 inhibitor, CyclA/E-Cdk2 complexes, PCNA, E2F-1
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