High-Intensity Raf Signal Causes Cell Cycle Arrest Mediated by p21Cip1
Open Access
- 1 September 1997
- journal article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 17 (9), 5588-5597
- https://doi.org/10.1128/mcb.17.9.5588
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.Keywords
This publication has 91 references indexed in Scilit:
- Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control proteinCurrent Biology, 1997
- Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4aCell, 1997
- Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryoCurrent Opinion in Genetics & Development, 1996
- PC12 cells overexpressing the insulin receptor undergo insulin-dependent neuronal differentiationCurrent Biology, 1994
- EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptorCurrent Biology, 1994
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993
- Activation of the MAP kinase pathway by the protein kinase rafCell, 1992
- Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53Cell, 1992
- Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2Cell, 1990
- Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirusNature, 1985