p53 regulates HSC quiescence. (A) Under homeostatic conditions, p53 regulates HSC quiescence mediated by Gfi-1 and Necdin and maintains HSC self-renewal by an unknown mechanism. (B) Under stress conditions, enhanced p53 activity promotes transcription of downstream targets, which trigger cell cycle arrest, senescence, or apoptosis. p53 also transactivates Pig genes, which induce ROS levels and promote p53 stability.