High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27Kip Cdk-complexes

Anja Groth; Berthe Marie Willumsen

doi:10.1016/j.cellsig.2004.11.021

High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27^Kip Cdk-complexes

Anja Groth, Berthe Marie Willumsen

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

8 Citationer (Scopus)

Abstract

Udgivelsesdato: September 2005

Originalsprog	Engelsk
Tidsskrift	Cellular Signalling
Vol/bind	17
Udgave nummer	9
Sider (fra-til)	1063-1073
ISSN	0898-6568
DOI	https://doi.org/10.1016/j.cellsig.2004.11.021
Status	Udgivet - 2005

Bibliografisk note

Keywords: Ras; High-density growth arrest; Cdk

Adgang til dokumentet

10.1016/j.cellsig.2004.11.021

Citationsformater

@article{0483cd606c3711dcbee902004c4f4f50,

title = "High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27Kip Cdk-complexes",

abstract = "The ras oncogene transforms immortalized, contact-inhibited non-malignant murine fibroblasts into cells that are focus forming, exhibit increased saturation density, and are malignant in suitable hosts. Here, we examined changes in cell cycle control complexes as normal and Ras-transformed cells ceased to grow exponentially, to reveal the molecular basis for Ras-dependent focus formation. As normal cells entered density-dependent arrest, cyclin D1 decreased while cyclin D2 was induced and replaced D1 in Cdk4 complexes. Concomitantly, p27Kip1 levels rose and the inhibitor accumulated in both Cdk4 and Cdk2 complexes, as these kinases were inactivated. Ras-transformed cells failed to arrest at normal saturation density and showed no significant alterations in cell control complexes at this point. Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent-like state with low Cdk4 and Cdk2 activity. Surprisingly, this delayed arrest was molecularly distinct from contact inhibition of normal cells, as it occurred in the absence of p27Kip1 induction and cyclin D1 levels remained high. This demonstrates that although oncogenic Ras efficiently disabled the normal response to contact inhibition, a separate back-up mechanism enforced cell cycle arrest at higher cell density.",

author = "Anja Groth and Willumsen, {Berthe Marie}",

note = "Keywords: Ras; High-density growth arrest; Cdk",

year = "2005",

doi = "10.1016/j.cellsig.2004.11.021",

language = "English",

volume = "17",

pages = "1063--1073",

journal = "Cellular Signalling",

issn = "0898-6568",

publisher = "Elsevier",

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TY - JOUR

T1 - High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27Kip Cdk-complexes

AU - Groth, Anja

AU - Willumsen, Berthe Marie

N1 - Keywords: Ras; High-density growth arrest; Cdk

PY - 2005

Y1 - 2005

N2 - The ras oncogene transforms immortalized, contact-inhibited non-malignant murine fibroblasts into cells that are focus forming, exhibit increased saturation density, and are malignant in suitable hosts. Here, we examined changes in cell cycle control complexes as normal and Ras-transformed cells ceased to grow exponentially, to reveal the molecular basis for Ras-dependent focus formation. As normal cells entered density-dependent arrest, cyclin D1 decreased while cyclin D2 was induced and replaced D1 in Cdk4 complexes. Concomitantly, p27Kip1 levels rose and the inhibitor accumulated in both Cdk4 and Cdk2 complexes, as these kinases were inactivated. Ras-transformed cells failed to arrest at normal saturation density and showed no significant alterations in cell control complexes at this point. Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent-like state with low Cdk4 and Cdk2 activity. Surprisingly, this delayed arrest was molecularly distinct from contact inhibition of normal cells, as it occurred in the absence of p27Kip1 induction and cyclin D1 levels remained high. This demonstrates that although oncogenic Ras efficiently disabled the normal response to contact inhibition, a separate back-up mechanism enforced cell cycle arrest at higher cell density.

AB - The ras oncogene transforms immortalized, contact-inhibited non-malignant murine fibroblasts into cells that are focus forming, exhibit increased saturation density, and are malignant in suitable hosts. Here, we examined changes in cell cycle control complexes as normal and Ras-transformed cells ceased to grow exponentially, to reveal the molecular basis for Ras-dependent focus formation. As normal cells entered density-dependent arrest, cyclin D1 decreased while cyclin D2 was induced and replaced D1 in Cdk4 complexes. Concomitantly, p27Kip1 levels rose and the inhibitor accumulated in both Cdk4 and Cdk2 complexes, as these kinases were inactivated. Ras-transformed cells failed to arrest at normal saturation density and showed no significant alterations in cell control complexes at this point. Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent-like state with low Cdk4 and Cdk2 activity. Surprisingly, this delayed arrest was molecularly distinct from contact inhibition of normal cells, as it occurred in the absence of p27Kip1 induction and cyclin D1 levels remained high. This demonstrates that although oncogenic Ras efficiently disabled the normal response to contact inhibition, a separate back-up mechanism enforced cell cycle arrest at higher cell density.

U2 - 10.1016/j.cellsig.2004.11.021

DO - 10.1016/j.cellsig.2004.11.021

M3 - Journal article

C2 - 15993748

SN - 0898-6568

VL - 17

SP - 1063

EP - 1073

JO - Cellular Signalling

JF - Cellular Signalling

IS - 9

ER -