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p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice

Rajareddy, Singareddy ; Reddy, Pradeep ; Du, Chun ; Liu, Lian ; Jagarlamudi, Krishna ; Tang, Wenli ; Shen, Yan ; Berthet, Cyril ; Peng, Stanford L. and Kaldis, Philipp LU orcid , et al. (2007) In Molecular Endocrinology 21(9). p.2189-2202
Abstract

In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase (Cdk) inhibitor 1B (commonly known as p27kip1 or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27-/-) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27+/+ mice. Moreover, in... (More)

In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase (Cdk) inhibitor 1B (commonly known as p27kip1 or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27-/-) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27+/+ mice. Moreover, in p27-/- ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27-/- ovaries was largely depleted, causing premature ovarian failure. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27 -/- ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9-caspase-3-caspase-7-poly (ADP-ribose) polymerase apoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans.

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publishing date
type
Contribution to journal
publication status
published
in
Molecular Endocrinology
volume
21
issue
9
pages
2189 - 2202
publisher
The Endocrine Society
external identifiers
  • scopus:34548351792
  • pmid:17565040
ISSN
0888-8809
DOI
10.1210/me.2007-0172
language
English
LU publication?
no
id
3278e843-fca0-4db5-923e-628baea29702
date added to LUP
2019-09-18 14:15:57
date last changed
2024-05-14 23:05:45
@article{3278e843-fca0-4db5-923e-628baea29702,
  abstract     = {{<p>In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase (Cdk) inhibitor 1B (commonly known as p27<sup>kip1</sup> or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27<sup>-/-</sup>) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27<sup>+/+</sup> mice. Moreover, in p27<sup>-/-</sup> ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27<sup>-/-</sup> ovaries was largely depleted, causing premature ovarian failure. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27 <sup>-/-</sup> ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9-caspase-3-caspase-7-poly (ADP-ribose) polymerase apoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans.</p>}},
  author       = {{Rajareddy, Singareddy and Reddy, Pradeep and Du, Chun and Liu, Lian and Jagarlamudi, Krishna and Tang, Wenli and Shen, Yan and Berthet, Cyril and Peng, Stanford L. and Kaldis, Philipp and Liu, Kui}},
  issn         = {{0888-8809}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{9}},
  pages        = {{2189--2202}},
  publisher    = {{The Endocrine Society}},
  series       = {{Molecular Endocrinology}},
  title        = {{p27<sup>kip1</sup> (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice}},
  url          = {{http://dx.doi.org/10.1210/me.2007-0172}},
  doi          = {{10.1210/me.2007-0172}},
  volume       = {{21}},
  year         = {{2007}},
}