THE ABSENCE OF P27KIP1, AN INHIBITOR OF G1 CYCLIN-DEPENDENT KINASES, UNCOUPLES DIFFERENTIATION AND GROWTH ARREST DURING THE GRANULOSA-GREATER-THAN LUTEAL TRANSITION
W. Tong et al., THE ABSENCE OF P27KIP1, AN INHIBITOR OF G1 CYCLIN-DEPENDENT KINASES, UNCOUPLES DIFFERENTIATION AND GROWTH ARREST DURING THE GRANULOSA-GREATER-THAN LUTEAL TRANSITION, Cell growth & differentiation, 9(9), 1998, pp. 787-794
The involvement of cyclin-dependent kinase inhibitors in differentiati
on remains unclear: are the roles of cyclin-dependent kinase inhibitor
s restricted to cell cycle arrest; or also required for completion of
the differentiation program; or both? Here, we report that differentia
tion of luteal cells can be uncoupled from growth arrest in p27-defici
ent mice. In these mice, female-specific infertility correlates with a
failure of embryos to implant at embryonic day 4.5. We show by ovaria
n transplant and hormone reconstitution experiments that failure to re
gulate luteal cell estradiol is one physiological mechanism for infert
ility in these mice. This failure is not due to a failure of p27-defic
ient granulosa cells to differentiate after hormonal stimulation; P450
scc, a marker for luteal progesterone biosynthesis, is expressed and g
ranulosa cell-specific cyclin D2 expression is reduced. However, unlik
e their wild-type counterparts, p27-deficient luteal cells continue to
proliferate for up to 3.5 days after hormonal stimulation. By day 5.5
, however, these cells withdraw from the cell cycle, suggesting that p
27 plays a role in the early events regulating withdrawal of cells fro
m the cell cycle. We have further shown that in the absence of this ti
mely withdrawal, estradiol regulation is perturbed, explaining in part
how fertility is compromised at the level of implantation, These data
support the interpretation of our previous observations on oligodendr
ocyte differentiation about a role for p27 in establishing the nonprol
iferative state, which in some cases (oligodendrocytes) is required fo
r differentiation, whereas in other cases it is required for the prope
r functioning of a differentiated cell (luteal cell).