Mice defective in p53 nuclear localization signal 1 exhibit exencephaly

p53 is a major suppressor of human malignancy. The protein levels and activity are tightly regulated in cells. Early experiments identified nuclear localization signal 1 (NLS1) as a regulator of p53 localization. We have generated mice bearing a mutation in p53 NLS1 , designated p53 NLS1 . Our experiments confirm a role for NLS1 in regulating p53 function. Murine embryonic fibroblasts generated from homozygous p53 NLS1 animals are partially defective in cell cycle arrest and do not respond to inhibitory signals from oncogenic Ras . In addition, p53-dependent apoptosis is abrogated in thymocytes. Contrary to predicted results, fibroblasts from homozygous p53 NLS1 animals have a greater rate of proliferation than p53 - null cells. In addition, p53 NLS1 cells are more resistant to UV-induced death. Surprisingly, the homozygous p53 NLS1 animals exhibit embryonic and peri-natal lethality, with a significant portion of the animals developing exencephaly. Thus, p53 NLS1/NLS1 embryos exhibit a reduced viability relative to p53 - null mice. These studies indicate that the NLS1 is a major regulator of p53 activity in vivo.