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.
(Less)
- author
- Kotoshiba, Shuhei
; Gopinathan, Lakshmi
; Pfeiffenberger, Elisabeth
; Rahim, Anisa
; Vardy, Leah A.
; Nakayama, Keiko
; Nakayama, Keiichi I.
and Kaldis, Philipp
LU
- publishing date
- 2014-02
- 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
-
- pmid:24269842
- scopus:84890748013
- 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
- 2024-06-26 03:24:25
@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}},
keywords = {{Cdk2; Cyclin-dependent kinase; Knockout mice; P27; Skp2}},
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}},
}