Inactivation of G2 checkpoint function and chromosomal destabilization are linked in human fibroblasts expressing human papillomavirus type 16 E6.
Chromosomal stability was linked to G2 checkpoint function in human fibroblasts expressing the human papillomavirus type 16 E6 oncoprotein. Soon after expression of E6, cells displayed an undamaged, diploid karyotype and normal mitotic delay after gamma-irradiation. As the E6-expressing cells aged through their in vitro life span, G2 checkpoint function diminished progressively. After 30-70 population doublings, 60-86% of the E6 cells displayed defective G2 checkpoint response. This attenuation of G2 checkpoint function was also associated with radiation-resistant cyclin B1/CDK1 protein kinase activity. Numerical and structural abnormalities of chromosomes developed in unirradiated E6 cells with kinetics that mirrored the loss of G2 checkpoint function. A significant correlation between inactivation of the G2 checkpoint and acquisition of chromosomal abnormalities was found, suggesting that the G2 checkpoint represents a barrier to genetic instability in cells lacking G1 checkpoint function.
Kaufmann
W K
WK
Department of Pathology and Laboratory Medicine, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7295, USA.
Schwartz
J L
JL
Hurt
J C
JC
Byrd
L L
LL
Galloway
D A
DA
Levedakou
E
E
Paules
R S
RS
D016203:CDC2 Protein Kinase / Q000032:analysis; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D016922:Cellular Senescence; D019457:Chromosome Breakage / Q000502:physiology*; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D004247:DNA / Q000032:analysis / Q000187:drug effects; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology / Q000528:radiation effects; D016195:G2 Phase / Q000502:physiology* / Q000528:radiation effects*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D016200:Maturation-Promoting Factor / Q000528:radiation effects; D008856:Microscopy, Fluorescence; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011003:Ploidies; D011419:Propidium / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D016196:S Phase; D008941:Spindle Apparatus / Q000502:physiology
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D011419:Propidium; D004247:DNA; D016203:CDC2 Protein Kinase; D016200:Maturation-Promoting Factor