Carcinogenesis, Vol 19, 1173-1183, Copyright © 1998 by Oxford University Press
AJ Gonzales, JG Christensen, RJ Preston, TL Goldsworthy, TD Tlsty and TR Fox
Non-genotoxic chemical carcinogens are capable of inducing tumors in
rodents without interacting with or directly altering the genetic material.
Since a preponderance of evidence suggests that cancer results from the
accumulation of genetic alterations, the mechanisms by which many
non-genotoxic carcinogens induce genotoxic events remain unclear. The
present study investigated whether the mitogenic, non- genotoxic carcinogen
phenobarbital (PB) could alter cell-cycle checkpoint controls, thereby
indirectly leading to the accumulation of genetic damage. Initial studies
involved characterizing cell-cycle checkpoint responses to DNA damage in
freshly isolated B6C3F1 mouse hepatocytes. These cells responded to
bleomycin-induced DNA damage by arresting in G1 and G2. Cell-cycle arrest
was coupled with p53 protein induction; however, p21WAF1 protein levels
remained unchanged. Studies that utilized hepatocytes isolated from C57BL
p53-/- mice showed that the DNA damage-induced G1 cell-cycle arrest was
dependent on p53 function, but cell-cycle arrest in G2 was not affected by
loss of p53. PB was able to delay and attenuate the G1 checkpoint response
without altering G2 checkpoint function. A reduction in p53 protein, but
not transcript levels, was observed in hepatocytes exposed to PB.
Additionally, PB delayed and attenuated p53 protein induction during DNA
damage, which suggests that changes in the p53 protein may be contributing
to the attenuated G1 checkpoint response caused by PB. Altered G1
checkpoint function represents an epigenetic mechanism by which
phenobarbital may prevent the detection and repair of DNA damage and
indirectly increase the frequency of genotoxic events above that occurring
spontaneously. Abrogation of checkpoint controls may, thus, play an
important mechanistic role in mitogenic, non-genotoxic chemical
carcinogenesis.
ARTICLES
Attenuation of G1 checkpoint function by the non-genotoxic carcinogen phenobarbital
Curriculum in Toxicology, University of North Carolina, Chapel Hill 27709, USA. Andrea.Gonzales@wl.com
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