Loss of SET reveals both the p53-dependent and the p53-independent functions in vivo

Our previous study showed that the oncoprotein SET acts as a new reader of unacetylated p53 for transcriptional repression. To further elucidate the physiological significance of SET in vivo, we generated set knockout mice. Set knockout mice died during embryonic development between day 11.5 and day 12.5 post coitum, exhibiting cardiac edema and open neural tube, among other developmental defects. Further analyses revealed that loss of SET leads to upregulation of p53 target genes including p21 and puma without any obvious effect on p53 stability in set knockout embryos. Notably, the developmental defects of set knockout mice were significantly, but nonetheless partially, rescued by concomitant deletion of p53. The failure to obtain fully live set/p53 double knockout mice suggested that p53-independent targets of SET also contribute to the embryonic lethality of set knockout mice. Indeed, we found that FOXO1 acts as an important target of SET and that SET-mediated regulation of FOXO1 is also acetylation-dependent. Taken together, these data underscore the importance of SET oncoprotein during embryonic development and reveal both of the p53-dependent and the p53-independent functions of SET in vivo.