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Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity
Matthew J. Kohn1,
Lyubomir T. Vassilev3,, and
Melvin L. DePamphilis1,4
1 National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA; 2 Ajinomoto Institute of Life Science, Kawasaki 210-8681, Japan; 3 Department of Discovery Oncology, Roche Research Center, Hoffmann–La Roche, Inc., Nutley, New Jersey 07110, USA
Genome endoreduplication during mammalian development is a rareevent for which the mechanism is unknown. It first appears whenfibroblast growth factor 4 (FGF4) deprivation induces differentiationof trophoblast stem (TS) cells into the nonproliferating trophoblastgiant (TG) cells required for embryo implantation. Here we showthat RO3306 inhibition of cyclin-dependent protein kinase 1(CDK1), the enzyme required to enter mitosis, induced differentiationof TS cells into TG cells. In contrast, RO3306 induced abortiveendoreduplication and apoptosis in embryonic stem cells, revealingthat inactivation of CDK1 triggers endoreduplication only incells programmed to differentiate into polyploid cells. Similarly,FGF4 deprivation resulted in CDK1 inhibition by overexpressingtwo CDK-specific inhibitors, p57/KIP2 and p21/CIP1. TS cellmutants revealed that p57 was required to trigger endoreduplicationby inhibiting CDK1, while p21 suppressed expression of the checkpointprotein kinase CHK1, thereby preventing induction of apoptosis.Furthermore, Cdk2–/– TS cells revealed that CDK2is required for endoreduplication when CDK1 is inhibited. Expressionof p57 in TG cells was restricted to G-phase nuclei to allowCDK activation of S phase. Thus, endoreduplication in TS cellsis triggered by p57 inhibition of CDK1 with concomitant suppressionof the DNA damage response by p21.