Δ40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs
Δ40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs
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DOI：
10.1101/gad.1987810
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发表时间：
2010-11-01
影响因子：
10.5
通讯作者：
Scrable, Heidi
中科院分区：
文献类型：
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作者：
Ungewitter, Erica;Scrable, Heidi
Delta 40 p53是肿瘤抑制因子p53的反式激活缺陷型。我们发现Delta 40 p53除了在胚胎干细胞（ESC）中高度表达外，还是小鼠胚胎发生早期阶段的主要p53亚型。通过改变ESC中Delta 40 p53的剂量，我们确定了这种亚型在维持ESC状态中的关键作用。Delta 40 p53的单倍不足导致ESC中多能性的丧失和体细胞周期的获得，而Delta 40 p53的剂量增加会抑制多能性并抑制向更分化状态的进展。Delta 40 p53通过控制全长p53在关键靶点（如Nanog和IGF-1受体（IGF-1 R））的活性来控制从多能ESC到分化体细胞的转换。IGF轴在ESC的多能性和分化之间的转换中起着核心作用，而Delta 40 p53通过控制IGF-1 R的水平，作为这个转换的主要调节器。我们认为这是Delta 40 p53在早期胚胎细胞和干细胞中的主要功能，这些细胞是表达这种同种型的唯一正常细胞。
Delta 40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that Delta 40p53, in addition to being highly expressed in embryonic stem cells (ESCs), is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of Delta 40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state. Haploinsufficiency for Delta 40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increased dosage of Delta 40p53 prolongs pluripotency and inhibits progression to a more differentiated state. Delta 40p53 controls the switch from pluripotent ESCs to differentiated somatic cells by controlling the activity of full-length p53 at critical targets such as Nanog and the IGF-1 receptor (IGF-1R). The IGF axis plays a central role in the switch between pluripotency and differentiation in ESCs-and Delta 40p53, by controlling the level of the IGF-1R, acts as a master regulator of this switch. We propose that this is the primary function of Delta 40p53 in cells of the early embryo and stem cells, which are the only normal cells in which this isoform is expressed.