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Cell‐cycle deregulation in BALB/c 3T3 cells transformed by 1,2‐dibromoethane and folpet pesticides
Author(s) -
Santucci Maria Alessandra,
Mercatali Laura,
Brusa Gianluca,
Pattacini Laura,
Barbieri Enza,
Perocco Paolo
Publication year - 2003
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.10162
Subject(s) - cell cycle , cyclin , cell cycle checkpoint , cyclin b , cyclin a2 , cyclin a , cancer research , biology , microbiology and biotechnology , g2 m dna damage checkpoint , cyclin d , cell , chemistry , genetics
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. Environ. Mol. Mutagen. 41:315–321, 2003. © 2003 Wiley‐Liss, Inc.