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.
Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01605, USA.
Anouk
A
Regeling
Heather L
HL
Armata
Judy
J
Gallant
Stephen N
SN
Jones
Hayla K
HK
Sluss
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D005347:Fibroblasts / Q000528:radiation effects; D005804:Genes, Lethal / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009436:Neural Tube Defects / Q000235:genetics*; D019913:Nuclear Localization Signals / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
D019913:Nuclear Localization Signals; D016159:Tumor Suppressor Protein p53