[E1A oncogene effect on the ability of p21(Waf1) to regulate G1/S arrest in E1A-expressing transformants following irradiation].
P21(Waf1) cyclin-dependent kinase inhibitor blocks cell cycle transition from G1 phase into DNA replication after DNA damage. The main targets of p21(Waf1) are Cyc 1E--Cdk2 and Cyc 1A--Cdk2 complexes, PCNA (proliferating cell nuclear antigen), a subunit of DNA polymerase delta, and E2F-1 transcription factor. The universal mechanism of cell cycle arrest in normal cells is determined as p21(Waf1) 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 p21(Waf1) 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 p21(Waf1) 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 p21(waf1) with the main regulators of G1-to-S transition, but is realized through other not yet identified ways.
Romanov
V S
VS
Brichkina
A I
AI
Pospelov
V A
VA
Pospelova
T V
TV
D017500:Adenovirus E1A Proteins; D000818:Animals; D002453:Cell Cycle; D002461:Cell Line, Transformed / Q000166:cytology / Q000528:radiation effects; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism / Q000502:physiology*; D016213:Cyclins / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D016193:G1 Phase / Q000528:radiation effects; D009857:Oncogenes; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016196:S Phase / Q000528:radiation effects; D013912:Threonine; D014965:X-Rays
D017500:Adenovirus E1A Proteins; D019925:Cyclin A; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D050687:E2F1 Transcription Factor; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D013912:Threonine; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2