Nuclear exclusion of p53 in a subset of tumors requires MDM2 function

Wild type p53 accumulates in the cytoplasm in a subset of tumors such as ne uroblastomas and breast carcinomas through an unknown mechanism. Exclusion of p53 from the nucleus may lead to inactivation of p53 during tumor develo pment. We present evidence that MDM2 plays a significant role in promoting the degradation of nuclear p53 in tumor cells with a cytoplasmic p53 phenot ype, Inhibition of MDM2 expression using antisense oligonucleotide, inhibit ion of MDM2 function by the tumor suppressor ARF or a MDM2 deletion mutant result in the accumulation of nuclear p53, p53 point mutants deficient in M DM2 binding have increased nuclear localization. Inhibition of nuclear expo rt by leptomycin B also results in retention of nascent p53 in the nucleus, suggesting that cytoplasmic distribution of p53 results from efficient exp ort of nuclear p53 in combination with MDM2-mediated degradation, These res ults suggest that MDM2 is an important determinant of p53 subcellular distr ibution and may contribute to p53 inactivation without overexpression.