PT  - JOURNAL ARTICLE
AU  - Sewing, A
AU  - Wiseman, B
AU  - Lloyd, A C
AU  - Land, H
TI  - High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.
AID  - 10.1128/MCB.17.9.5588
DP  - 1997 Sep 01
TA  - Molecular and Cellular Biology
PG  - 5588--5597
VI  - 17
IP  - 9
4099  - http://mcb.asm.org/content/17/9/5588.short
4100  - http://mcb.asm.org/content/17/9/5588.full
SO  - Mol. Cell. Biol.1997 Sep 01; 17
AB  - 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.