The p53 signal transduction pathway is intact in human neuroblastoma despite cytoplasmic localization.
Mutations of the p53 tumor suppressor gene are rarely found in neuroblastoma. Though typically a nuclear protein, a number of tumor cell types have recently been reported to exhibit cytoplasmic p53 immunostaining, and it has been suggested that altered cellular localization is another mechanism of inhibiting p53 function. We examined p53 protein expression, localization, and function in neuroblastoma cell lines with wild-type p53 genes. Basal p53 levels were largely confined to the cytoplasmic compartment in these cells. However, after irradiation, p53 protein levels increased predominately in the nucleus. Transcriptional activity of p53 was intact in these cells because "downstream" proteins, p21WAF1 and MDM2, were induced by irradiation. In contrast to a neuroblastoma cell line harboring a mutant p53 gene, the neuroblastoma cells with wild-type protein were associated with an intact G1 arrest after DNA damage. The induced nuclear protein in these neuroblastoma cells also appeared functional as measured by its capacity to bind to a DNA oligomer containing a p53-consensus sequence. We have concluded that although p53 expression in neuroblastoma cells is primarily localized to the cytosol, ionizing radiation induces a functional p53 protein in the nucleus and that this cytoplasmic sequestration of p53 in human neuroblastoma is not a mechanism of inactivating p53 function.
Goldman
S C
SC
Johns Hopkins Oncology Center, Baltimore, Maryland, USA.
Chen
C Y
CY
Lansing
T J
TJ
Gilmer
T M
TM
Kastan
M B
MB
D015153:Blotting, Western; D002453:Cell Cycle / Q000528:radiation effects; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics; D016158:Genes, p53 / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry; D009447:Neuroblastoma / Q000737:chemistry* / Q000473:pathology*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000235:genetics / Q000502:physiology*
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53