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FOXO target gene CTDSP2 regulates cell cycle progression through Ras and p21(Cip1/Waf1).

Kloet DE, Polderman PE, Eijkelenboom A, Smits LM, van Triest MH, van den Berg MC, Groot Koerkamp MJ, van Leenen D, Lijnzaad P, Holstege FC, Burgering BM - Biochem. J. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: University Medical Centre Utrecht, Universiteitsweg 100 STR3.217, 3584CG Utrecht, The Netherlands.

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A common set of FOXO-regulated genes in human and mouse cell lines overexpressing FOXO3 or FOXO4FOXO3 and FOXO4 induced changes in HUVECs and UMRC2, RCC4, BaF3, DLD1-derived DL23 [19] and HEK-293T cells were compared. Depicted are genes statistically significantly (P<0.05) regulated in relevant datasets (see the Materials and methods section for details). Asterisks indicate genes that are statistically significantly (ANOVA, P<0.05) regulated by PI3K or PKB/Akt activation, in opposing direction compared with FOXO3/4 activation. The right-hand side shows the distance of the closest FOXO3 peak in DL23 cells deduced from [27].
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Figure 1: A common set of FOXO-regulated genes in human and mouse cell lines overexpressing FOXO3 or FOXO4FOXO3 and FOXO4 induced changes in HUVECs and UMRC2, RCC4, BaF3, DLD1-derived DL23 [19] and HEK-293T cells were compared. Depicted are genes statistically significantly (P<0.05) regulated in relevant datasets (see the Materials and methods section for details). Asterisks indicate genes that are statistically significantly (ANOVA, P<0.05) regulated by PI3K or PKB/Akt activation, in opposing direction compared with FOXO3/4 activation. The right-hand side shows the distance of the closest FOXO3 peak in DL23 cells deduced from [27].

Mentions: Active FOXO proteins affect a number of cellular processes (reviewed in [2]). To identify genes transcriptionally controlled by FOXO proteins that convey the regulation of these processes, different studies including the present one have generated microarray datasets [3–6]. These studies identified numerous FOXO target genes which, when analysed under different conditions, are shown to be regulated only in a particular context or cell type. To identify a set of FOXO3- and FOXO4-regulated genes that is common to at least a limited number of cell types, we merged microarray datasets of FOXO3- or FOXO4-induced expression changes in HUVECs (human umbilical vein endothelial cells), UMRC2, RCC4, BaF3, DLD1-derived DL23 [19] and HEK-293T cells (see the Supplementary methods for details). We found ten genes that are regulated in all datasets and focused on genes that are increased upon FOXO activation, because we have recently published that FOXO activation correlates best with increased expression of genes [27]. Of the six genes found to be statistically significantly (P<0.05) up-regulated in all datasets, CITED2 and PINK1 have been previously described to be FOXO target genes [29,30]. Besides these, CTDSP2 is the most strongly regulated gene in these datasets, but has not been described as a FOXO target gene to date. Interestingly, CTDSP2 expression is decreased significantly (ANOVA, P<0.05) in response to activation of PI3K or PKB/Akt (Figure 1; two rightmost columns), suggesting that CTDSP2 expression is highly sensitive to FOXO activity.


FOXO target gene CTDSP2 regulates cell cycle progression through Ras and p21(Cip1/Waf1).

Kloet DE, Polderman PE, Eijkelenboom A, Smits LM, van Triest MH, van den Berg MC, Groot Koerkamp MJ, van Leenen D, Lijnzaad P, Holstege FC, Burgering BM - Biochem. J. (2015)

A common set of FOXO-regulated genes in human and mouse cell lines overexpressing FOXO3 or FOXO4FOXO3 and FOXO4 induced changes in HUVECs and UMRC2, RCC4, BaF3, DLD1-derived DL23 [19] and HEK-293T cells were compared. Depicted are genes statistically significantly (P<0.05) regulated in relevant datasets (see the Materials and methods section for details). Asterisks indicate genes that are statistically significantly (ANOVA, P<0.05) regulated by PI3K or PKB/Akt activation, in opposing direction compared with FOXO3/4 activation. The right-hand side shows the distance of the closest FOXO3 peak in DL23 cells deduced from [27].
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: A common set of FOXO-regulated genes in human and mouse cell lines overexpressing FOXO3 or FOXO4FOXO3 and FOXO4 induced changes in HUVECs and UMRC2, RCC4, BaF3, DLD1-derived DL23 [19] and HEK-293T cells were compared. Depicted are genes statistically significantly (P<0.05) regulated in relevant datasets (see the Materials and methods section for details). Asterisks indicate genes that are statistically significantly (ANOVA, P<0.05) regulated by PI3K or PKB/Akt activation, in opposing direction compared with FOXO3/4 activation. The right-hand side shows the distance of the closest FOXO3 peak in DL23 cells deduced from [27].
Mentions: Active FOXO proteins affect a number of cellular processes (reviewed in [2]). To identify genes transcriptionally controlled by FOXO proteins that convey the regulation of these processes, different studies including the present one have generated microarray datasets [3–6]. These studies identified numerous FOXO target genes which, when analysed under different conditions, are shown to be regulated only in a particular context or cell type. To identify a set of FOXO3- and FOXO4-regulated genes that is common to at least a limited number of cell types, we merged microarray datasets of FOXO3- or FOXO4-induced expression changes in HUVECs (human umbilical vein endothelial cells), UMRC2, RCC4, BaF3, DLD1-derived DL23 [19] and HEK-293T cells (see the Supplementary methods for details). We found ten genes that are regulated in all datasets and focused on genes that are increased upon FOXO activation, because we have recently published that FOXO activation correlates best with increased expression of genes [27]. Of the six genes found to be statistically significantly (P<0.05) up-regulated in all datasets, CITED2 and PINK1 have been previously described to be FOXO target genes [29,30]. Besides these, CTDSP2 is the most strongly regulated gene in these datasets, but has not been described as a FOXO target gene to date. Interestingly, CTDSP2 expression is decreased significantly (ANOVA, P<0.05) in response to activation of PI3K or PKB/Akt (Figure 1; two rightmost columns), suggesting that CTDSP2 expression is highly sensitive to FOXO activity.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: University Medical Centre Utrecht, Universiteitsweg 100 STR3.217, 3584CG Utrecht, The Netherlands.

Show MeSH
Related in: MedlinePlus