Development of mice without Cip/Kip CDK inhibitors

Yuki Tateishi, Akinobu Matsumoto, Tomoharu Kanie, Eiji Hara, Keiko Nakayama, Keiichi Nakayama

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Timely exit of cells from the cell cycle is essential for proper cell differentiation during embryogenesis. Cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family (p21, p27, and p57) are negative regulators of cell cycle progression and are thought to be essential for development. However, the extent of functional redundancy among Cip/Kip family members has remained largely unknown. We have now generated mice that lack all three Cip/Kip CKIs (TKO mice) and compared them with those lacking each possible pair of these proteins (DKO mice). We found that the TKO embryos develop normally until midgestation but die around embryonic day (E) 13.5, slightly earlier than p27/p57 DKO embryos. The TKO embryos manifested morphological abnormalities as well as increased rates of cell proliferation and apoptosis in the placenta and lens that were essentially indistinguishable from those of p27/p57 DKO mice. Unexpectedly, the proliferation rate and cell cycle profile of mouse embryonic fibroblasts (MEFs) lacking all three Cip/Kip CKIs did not differ substantially from those of control MEFs. The abundance and kinase activity of CDK2 were markedly increased, whereas CDK4 activity and cyclin D1 abundance were decreased, in both p27/p57 DKO and TKO MEFs during progression from G0 to S phase compared with those in control MEFs. The extents of the increase in CDK2 activity and the decrease in CDK4 activity and cyclin D1 abundance were greater in TKO MEFs than in p27/p57 DKO MEFs. These results suggest that p27 and p57 play an essential role in mouse development after midgestation, and that p21 plays only an auxiliary role in normal development (although it is thought to be a key player in the response to DNA damage).

Original languageEnglish
Pages (from-to)285-292
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume427
Issue number2
DOIs
Publication statusPublished - Oct 19 2012

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Cyclin-Dependent Kinases
Fibroblasts
Cyclin D1
Cells
Cell Cycle
Embryonic Structures
Cell proliferation
Redundancy
Lenses
Phosphotransferases
Apoptosis
DNA
S Phase
Placenta
DNA Damage
Embryonic Development
Cell Differentiation
Proteins
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Development of mice without Cip/Kip CDK inhibitors. / Tateishi, Yuki; Matsumoto, Akinobu; Kanie, Tomoharu; Hara, Eiji; Nakayama, Keiko; Nakayama, Keiichi.

In: Biochemical and Biophysical Research Communications, Vol. 427, No. 2, 19.10.2012, p. 285-292.

Research output: Contribution to journalArticle

Tateishi, Yuki ; Matsumoto, Akinobu ; Kanie, Tomoharu ; Hara, Eiji ; Nakayama, Keiko ; Nakayama, Keiichi. / Development of mice without Cip/Kip CDK inhibitors. In: Biochemical and Biophysical Research Communications. 2012 ; Vol. 427, No. 2. pp. 285-292.
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