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Vol. 9, Issue 4, 795-807, April 1998
and
*Department of Anatomy, University of California, San Francisco,
California 94143-0750; and
Differentiation of trophoblast giant cells in the rodent placenta
is accompanied by exit from the mitotic cell cycle and onset of
endoreduplication. Commitment to giant cell differentiation is under
developmental control, involving down-regulation of Id1 and Id2, concomitant with up-regulation of the basic
helix-loop-helix factor Hxt and acquisition of increased
adhesiveness. Endoreduplication disrupts the alternation of DNA
synthesis and mitosis that maintains euploid DNA content during
proliferation. To determine how the mammalian endocycle is regulated,
we examined the expression of the cyclins and cyclin-dependent kinases
during the transition from replication to endoreduplication in the
Rcho-1 rat choriocarcinoma cell line. We cultured these cells under
conditions that gave relatively synchronous endoreduplication. This
allowed us to study the events that occur during the transition from
the mitotic cycle to the first endocycle. With giant cell
differentiation, the cells switched cyclin D isoform expression from D3
to D1 and altered several checkpoint functions, acquiring a relative
insensitivity to DNA-damaging agents and a coincident serum
independence. The initiation of S phase during endocycles appeared to
involve cycles of synthesis of cyclins E and A, and termination of S
was associated with abrupt loss of cyclin A and E. Both cyclins were
absent from gap phase cells, suggesting that their degradation may be
necessary to allow reinitiation of the endocycle. The arrest of the
mitotic cycle at the onset of endoreduplication was associated with a failure to assemble cyclin B/p34cdk1 complexes during the
first endocycle. In subsequent endocycles, cyclin B expression was
suppressed. Together these data suggest several points at which cell
cycle regulation could be targeted to shift cells from a mitotic to an
endoreduplicative cycle.
Samuel Lunenfeld Research
Institute Mount Sinai Hospital and Departments of Obstetrics and
Gynecology, and Molecular and Medical Genetics, University of Toronto,
Toronto, Ontario M5G 1X5, Canada
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