FOXO target gene CTDSP2 regulates cell cycle progression through Ras and p21(Cip1/Waf1).
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.
Affiliation: University Medical Centre Utrecht, Universiteitsweg 100 STR3.217, 3584CG Utrecht, The Netherlands.Show MeSH
Related in: MedlinePlus
Mentions: To establish the kinetics of CTDSP2 regulation, we measured CTDSP2 mRNA levels in response to activation of FOXO3.A3-ER in DL23 cells. We observed a rapid increase in CTDSP2 mRNA levels after addition of 4OHT (Figure 2A), even in the presence of the protein translation inhibitor cycloheximide (Figure 2B), both strong indications that FOXO3 can directly control CTDSP2 expression. Furthermore, in DLD1, U2OS, RPE and NIH/3T3 cells, expression of CTDSP2 mRNA is increased in response to inhibitors of PI3K or PKB/Akt (Figure 2C and Supplementary Figure S1A), which are known to control the activity of endogenous FOXO proteins . Interestingly, CTDSP2 regulation is not restricted to FOXO3, as ectopic expression of GFP–FOXO1, GFP–FOXO3 or GFP–FOXO4 also elevates CTDSP2 mRNA levels in U2OS cells (Supplementary Figure S1B). Lastly, shRNA-mediated knockdown of FOXO1 and FOXO3 in U2OS cells decreases the basal and PKB/Akt-inhibition-induced increase in CTDSP2 mRNA (Supplementary Figure S1C), showing that endogenous FOXO1 and FOXO3 are involved in the control of CTDSP2 expression levels.
Affiliation: University Medical Centre Utrecht, Universiteitsweg 100 STR3.217, 3584CG Utrecht, The Netherlands.