Δ40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs

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.