Cell-cycle deregulation in BALB/c 3T3 cells transformed by 1,2-dibromoethane and folpet pesticides.
The cell-transforming potential of 1,2-dibromoethane and folpet, two widely used agricultural pesticides that are potential sources of environmental pollution, has been previously ascribed to their promoting activity. In this study, we investigated whether BALB/c 3T3 transformation by these chemicals was associated with the deregulation of signals involved in cell-cycle progression and in cell-cycle checkpoint induction. We found that two BALB/c 3T3 cell clones transformed by in vitro medium-term (8-week) exposure to the carcinogens had a constitutive acceleration of cell transition from G(1) to S phase and an abrogation of the radiation-induced G(1)/S checkpoint. These events involved multiple signals; in particular, the inhibitors of cyclin/cyclin-dependent kinase complexes p21 and p27 were significantly down-modulated and the positive regulators of cell-cycle progression cyclin D(3) and E were up-modulated. As anticipated for cells where the G(1)/S checkpoint was abrogated, the transformed cells exhibited a significant reinforcement of the radiation-induced G(2)/M checkpoint, the only checkpoint remaining to protect genomic integrity. However, cyclin A(1) and B(1) coexpression and cyclin A(1) overexpression were found despite the G2 arrest in irradiated cells and these signals likely attenuate the G(2)/M checkpoint. These alterations to normal cell cycling may promote the emergence of both numerical and structural chromosomal abnormalities and their tolerance. Such a condition could play a key role in neoplastic transformation and be crucial in tumor progression. Furthermore, cyclin A(1) overexpression may play an autonomous role in the neoplastic transformation of BALB/c 3T3 cells, as it does in other cell types of mesenchymal origin.
Santucci
Maria Alessandra
MA
Dipartimento di Patologia Sperimentale, Sezione di Cancerologia, Università di Bologna, Italy. ssantucc@med.unibo.it
Mercatali
Laura
L
Brusa
Gianluca
G
Pattacini
Laura
L
Barbieri
Enza
E
Perocco
Paolo
P
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D019925:Cyclin A / Q000187:drug effects / Q000378:metabolism; D056750:Cyclin A1; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D015946:Ethylene Dibromide / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects* / Q000528:radiation effects; D016193:G1 Phase / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010575:Pesticides / Q000633:toxicity*; D010797:Phthalimides / Q000633:toxicity*; D016196:S Phase / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
C503747:Ccna1 protein, mouse; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056750:Cyclin A1; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D010575:Pesticides; D010797:Phthalimides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015946:Ethylene Dibromide; C005020:folpet