p53 Activation Paradoxically Causes Liver Cancer

Activation of p53 regulates a transcriptional program that can cause cell cycle arrest, senescence, apoptosis, and ferroptosis, which are potent tumor suppressive mechanisms. Unexpectedly, Makino and colleagues show in this issue of Cancer Research that the constitutive activation of p53 in murine hepatocytes leads to tumor development. Detailed analyses indicate that p53 activation leads to loss of hepatocytes, increased expression of chemokines and humoral factors, and expansion of the hepatic progenitor cell population. These progenitor cells are highly proliferative, show chromosomal instability, and eventually transform. In chronic liver disease in humans, activation of p53 is associated with increased liver cancer development. This study highlights the complexity and non-cell autonomous nature of the physiologic p53 response.