Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota 55905, USA.
Genes Dev. 2010 Nov 1;24(21):2408-19. doi: 10.1101/gad.1987810.
Δ40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that Δ40p53, 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 Δ40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state. Haploinsufficiency for Δ40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increased dosage of Δ40p53 prolongs pluripotency and inhibits progression to a more differentiated state. Δ40p53 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 Δ40p53, 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 Δ40p53 in cells of the early embryo and stem cells, which are the only normal cells in which this isoform is expressed.
Δ40p53 是肿瘤抑制因子 p53 的一种转录激活缺陷型异构体。我们发现，Δ40p53 不仅在胚胎干细胞（ESCs）中高度表达，还是小鼠胚胎发生早期的主要 p53 异构体。通过改变 ESCs 中 Δ40p53 的剂量，我们确定了该异构体在维持 ESC 状态中的关键作用。Δ40p53 的单倍不足导致 ESCs 的多能性丧失和体细胞周期的获得，而 Δ40p53 的剂量增加则延长了多能性并抑制了向更分化状态的进展。Δ40p53 通过控制全长 p53 在关键靶标（如 Nanog 和 IGF-1 受体（IGF-1R））的活性，控制从多能性 ESCs 到分化体细胞的转变，从而控制着从多能性 ESCs 到分化体细胞的转变。IGF 轴在 ESCs 中的多能性和分化之间的转变中起着核心作用-通过控制 IGF-1R 的水平，Δ40p53 作为这种转变的主调控因子。我们提出，这是 Δ40p53 在早期胚胎和干细胞中的主要功能，而这种异构体仅在这些正常细胞中表达。
