Abstract
Activity of FOXO (forkhead box O) transcription factors is inhibited by growth factor-PI3K (phosphoinositide 3-kinase)-PKB (protein kinase B)/Akt signalling to control a variety of cellular processes including cell cycle progression. Through comparative analysis of a number of microarray datasets we identified a set of genes commonly regulated by FOXO proteins and PI3K-PKB/Akt, which includes CTDSP2 (C-terminal domain small phosphatase 2). We validated CTDSP2 as a genuine FOXO target gene and show that ectopic CTDSP2 can induce cell cycle arrest. We analysed transcriptional regulation after CTDSP2 expression and identified extensive regulation of genes involved in cell cycle progression, which depends on the phosphatase activity of CTDSP2. The most notably regulated gene is the CDK (cyclin-dependent kinase) inhibitor p21(Cip1/Waf1) and in the present study we show that p21(Cip1/Waf1) is partially responsible for the cell cycle arrest through decreasing cyclin-CDK activity. Our data suggest that CTDSP2 induces p21(Cip1/Waf1) through increasing the activity of Ras. As has been described previously, Ras induces p21(Cip1/Waf1) through p53-dependent and p53-independent pathways and indeed both p53 and MEK inhibition can mitigate the CTDSP2-induced p21(Cip1/Waf1) mRNA up-regulation. In support of Ras activation by CTDSP2, depletion of endogenous CTDSP2 results in reduced Ras activity and thus CTDSP2 seems to be part of a larger set of genes regulated by FOXO proteins, which increase growth factor signalling upon FOXO activation.
Highlights
The forkhead box transcription factors are a large family of transcription factors characterized by a conserved DNA-binding domain: the forkhead box
We find that CTDSP2 is a direct target gene of forkhead box O (FOXO) proteins with FOXO-binding sites directly adjacent to the transcriptional start site (TSS) of CTDSP2, which are sufficient for transactivation
We show that CTDSP2 is regulated by FOXO1, FOXO3 and FOXO4 and its expression is highly sensitive to phosphoinositide 3-kinase (PI3K)–protein kinase B (PKB)/Akt–FOXO signalling
Summary
The forkhead box transcription factors are a large family of transcription factors characterized by a conserved DNA-binding domain: the forkhead box. To identify genes transcriptionally controlled by FOXO, which are critical in mediating the FOXO proteins’ effect on lifespan, a number of laboratories have used microarrays to explore mRNA changes after FOXO activation (the present study and [3,4,5,6]). These studies show that a large part of FOXO transcriptional output is highly context-dependent and FOXO regulation of most genes is only observed in a limited number of settings or cell types. Members of the CTDSP family of phosphatases are involved in regulation of both signalling and transcription
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