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p27 is regulated independently of Skp2 in the absence of Cdk2

Kotoshiba, Shuhei ; Gopinathan, Lakshmi ; Pfeiffenberger, Elisabeth ; Rahim, Anisa ; Vardy, Leah A. ; Nakayama, Keiko ; Nakayama, Keiichi I. and Kaldis, Philipp LU (2014) In Biochimica et Biophysica Acta - Molecular Cell Research 1843(2). p.436-445
Abstract

Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdks. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27Kip1, which is able to inhibit Cdk2 and Cdk1. Knockdown of Cdk2 abrogated proliferation of Skp2-/- mouse embryonic fibroblasts, encouraging us to generate Cdk2-/-Skp2-/- double knockout mice. Cdk2-/-Skp2-/- double knockout mice are viable and display similar phenotypes as Cdk2-/- and Skp2-/- mice. Unexpectedly, fibroblasts generated from... (More)

Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdks. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27Kip1, which is able to inhibit Cdk2 and Cdk1. Knockdown of Cdk2 abrogated proliferation of Skp2-/- mouse embryonic fibroblasts, encouraging us to generate Cdk2-/-Skp2-/- double knockout mice. Cdk2-/-Skp2-/- double knockout mice are viable and display similar phenotypes as Cdk2-/- and Skp2-/- mice. Unexpectedly, fibroblasts generated from Cdk2-/-Skp2-/- double knockout mice proliferated at normal rates. The increased stability of p27 observed in Skp2-/- MEFs was not observed in Cdk2-/-Skp2-/- double knockout fibroblasts indicating that in the absence of Cdk2, p27 is regulated by Skp2-independent mechanisms. Ablation of other ubiquitin ligases for p27 such as KPC1, DDB1, and Pirh2 did not restore stability of p27 in Cdk2-/-Skp2-/- MEFs. Our findings point towards novel and alternate pathways for p27 regulation.

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author
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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cdk2, Cyclin-dependent kinase, Knockout mice, P27, Skp2
in
Biochimica et Biophysica Acta - Molecular Cell Research
volume
1843
issue
2
pages
436 - 445
publisher
Elsevier
external identifiers
  • scopus:84890748013
  • pmid:24269842
ISSN
0167-4889
DOI
10.1016/j.bbamcr.2013.11.005
language
English
LU publication?
no
id
287e113c-3b1e-4f70-b7ee-6e3c45418717
date added to LUP
2019-09-18 13:56:24
date last changed
2020-01-30 03:54:39
@article{287e113c-3b1e-4f70-b7ee-6e3c45418717,
  abstract     = {<p>Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdks. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27<sup>Kip1</sup>, which is able to inhibit Cdk2 and Cdk1. Knockdown of Cdk2 abrogated proliferation of Skp2<sup>-/-</sup> mouse embryonic fibroblasts, encouraging us to generate Cdk2<sup>-/-</sup>Skp2<sup>-/-</sup> double knockout mice. Cdk2<sup>-/-</sup>Skp2<sup>-/-</sup> double knockout mice are viable and display similar phenotypes as Cdk2<sup>-/-</sup> and Skp2<sup>-/-</sup> mice. Unexpectedly, fibroblasts generated from Cdk2<sup>-/-</sup>Skp2<sup>-/-</sup> double knockout mice proliferated at normal rates. The increased stability of p27 observed in Skp2<sup>-/-</sup> MEFs was not observed in Cdk2<sup>-/-</sup>Skp2<sup>-/-</sup> double knockout fibroblasts indicating that in the absence of Cdk2, p27 is regulated by Skp2-independent mechanisms. Ablation of other ubiquitin ligases for p27 such as KPC1, DDB1, and Pirh2 did not restore stability of p27 in Cdk2<sup>-/-</sup>Skp2<sup>-/-</sup> MEFs. Our findings point towards novel and alternate pathways for p27 regulation.</p>},
  author       = {Kotoshiba, Shuhei and Gopinathan, Lakshmi and Pfeiffenberger, Elisabeth and Rahim, Anisa and Vardy, Leah A. and Nakayama, Keiko and Nakayama, Keiichi I. and Kaldis, Philipp},
  issn         = {0167-4889},
  language     = {eng},
  number       = {2},
  pages        = {436--445},
  publisher    = {Elsevier},
  series       = {Biochimica et Biophysica Acta - Molecular Cell Research},
  title        = {p27 is regulated independently of Skp2 in the absence of Cdk2},
  url          = {http://dx.doi.org/10.1016/j.bbamcr.2013.11.005},
  doi          = {10.1016/j.bbamcr.2013.11.005},
  volume       = {1843},
  year         = {2014},
}