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PMID: 9271434 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.

Molecular and cellular biology ·Vol. 17 ·No. 9 ·1997-09-00 ·Pages 5588-97

Sewing A, Wiseman B, Lloyd AC, Land H

Abstract

Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.

MeSH Terms
3T3 Cells Animals Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Cycle Cyclin-Dependent Kinase Inhibitor p21 Cyclins/metabolism Enzyme Inhibitors/metabolism Fibroblasts/cytology,metabolism G1 Phase Mice Oncogene Proteins v-raf Protein-Tyrosine Kinases/metabolism Retroviridae Proteins, Oncogenic/metabolism Signal Transduction ras Proteins/metabolism
Chemicals
Cdkn1a protein, mouse Cyclin-Dependent Kinase Inhibitor p21 Cyclins Enzyme Inhibitors Retroviridae Proteins, Oncogenic Protein-Tyrosine Kinases Oncogene Proteins v-raf Calcium-Calmodulin-Dependent Protein Kinases ras Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Sewing A
Imperial Cancer Research Fund, London, United Kingdom.
Wiseman B
Lloyd A C
Land H
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.9.5588
Published
1997-09-00
Pages
5588-97
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC232407
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.17.9.5588 PMC Full Text View journal details
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