Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China.
Cell Death Dis. 2019 Mar 11;10(3):237. doi: 10.1038/s41419-019-1484-6.
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.
我们之前的研究表明，癌蛋白 SET 作为一个新的非乙酰化 p53 的转录抑制物的阅读器。为了进一步阐明 SET 在体内的生理意义，我们生成了 set 敲除小鼠。set 敲除小鼠在胚胎发育期间死亡，大约在妊娠后第 11.5 天到第 12.5 天，表现出心脏水肿和神经管未闭等发育缺陷。进一步的分析表明，SET 的缺失导致 p53 靶基因（包括 p21 和 puma）的上调，而对 set 敲除胚胎中 p53 的稳定性没有明显影响。值得注意的是，p53 的缺失部分挽救了 set 敲除小鼠的发育缺陷。未能获得完全存活的 set/p53 双重敲除小鼠表明，SET 的 p53 非依赖性靶标也导致了 set 敲除小鼠的胚胎致死性。事实上，我们发现 FOXO1 是 SET 的一个重要靶标，并且 SET 对 FOXO1 的调节也是依赖于乙酰化的。总之，这些数据强调了 SET 癌蛋白在胚胎发育过程中的重要性，并揭示了 SET 在体内的 p53 依赖性和非依赖性功能。
