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Vol. 11, Issue 3, 1037-1045, March 2000
*Program in Development and Fetal Health, Samuel Lunenfeld Research
Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; and
Endoreduplication is an unusual form of cell cycle in which rounds
of DNA synthesis repeat in the absence of intervening mitoses. How G1/S
cyclin-dependent kinase (Cdk) activity is regulated during the
mammalian endocycle is poorly understood. We show here that expression
of the G1/S Cdk inhibitor p57Kip2 is induced coincidentally
with the transition to the endocycle in trophoblast giant cells.
Kip2 mRNA is constitutively expressed during subsequent
endocycles, but the protein level fluctuates. In trophoblast giant
cells synchronized for the first few endocycles, the
p57Kip2 protein accumulates only at the end of S-phase and
then rapidly disappears a few hours before the onset of the next
S-phase. The protein becomes stabilized by mutation of a C-terminal Cdk
phosphorylation site. As a consequence, introduction of this stable
form of p57Kip2 into giant cells blocks S-phase entry.
These data imply that p57Kip2 is subject to
phosphorylation-dependent turnover. Surprisingly, although this occurs
in endoreduplicating giant cells, p57Kip2 is stable when
ectopically expressed in proliferating trophoblast cells, indicating
that these cells lack the mechanism for protein targeting and/or
degradation. These data show that the appearance of p57Kip2
punctuates the completion of DNA replication, whereas its turnover is
subsequently required to initiate the next round of endoreduplication in trophoblast giant cells. Cyclical expression of a Cdk inhibitor, by
terminating G1/S Cdk activity, may help promote the resetting of DNA
replication machinery.
Departments of Obstetrics and Gynaecology and Molecular
and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X5,
Canada
Corresponding author. E-mail address:
cross{at}mshri.on.ca.
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