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

被引:68
作者
Lu, WG
Pochampally, R
Chen, LH
Traidej, M
Wang, YL
Chen, JD
机构
[1] H Lee Moffitt Canc Ctr & Res Inst, Mol Oncol Program, Tampa, FL 33612 USA
[2] Louisiana State Univ, Med Ctr, Dept Microbiol, New Orleans, LA 70112 USA
关键词
MDM2; p53; ARF; antisense oligodeoxynucleotide; leptomycin B; tumor suppressor;
D O I
10.1038/sj.onc.1203262
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Wild type p53 accumulates in the cytoplasm in a subset of tumors such as neuroblastomas and breast carcinomas through an unknown mechanism. Exclusion of p53 from the nucleus may lead to inactivation of p53 during tumor development. We present evidence that MDM2 plays a significant role in promoting the degradation of nuclear p53 in tumor cells with a cytoplasmic p53 phenotype, Inhibition of MDM2 expression using antisense oligonucleotide, inhibition 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 MDM2 binding have increased nuclear localization. Inhibition of nuclear export by leptomycin B also results in retention of nascent p53 in the nucleus, suggesting that cytoplasmic distribution of p53 results from efficient export of nuclear p53 in combination with MDM2-mediated degradation, These results suggest that MDM2 is an important determinant of p53 subcellular distribution and may contribute to p53 inactivation without overexpression.
引用
收藏
页码:232 / 240
页数:9
相关论文
共 52 条
[1]   SUPPRESSION OF HUMAN COLORECTAL-CARCINOMA CELL-GROWTH BY WILD-TYPE-P53 [J].
BAKER, SJ ;
MARKOWITZ, S ;
FEARON, ER ;
WILLSON, JKV ;
VOGELSTEIN, B .
SCIENCE, 1990, 249 (4971) :912-915
[2]   Enhanced phosphorylation of p53 by ATN in response to DNA damage [J].
Banin, S ;
Moyal, L ;
Shieh, SY ;
Taya, Y ;
Anderson, CW ;
Chessa, L ;
Smorodinsky, NI ;
Prives, C ;
Reiss, Y ;
Shiloh, Y ;
Ziv, Y .
SCIENCE, 1998, 281 (5383) :1674-1677
[3]   MDM2 EXPRESSION IS INDUCED BY WILD TYPE-P53 ACTIVITY [J].
BARAK, Y ;
JUVEN, T ;
HAFFNER, R ;
OREN, M .
EMBO JOURNAL, 1993, 12 (02) :461-468
[4]   The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis [J].
Brown, DR ;
Thomas, CA ;
Deb, SP .
EMBO JOURNAL, 1998, 17 (09) :2513-2525
[5]   Activation of the ATM kinase by ionizing radiation and phosphorylation of p53 [J].
Canman, CE ;
Lim, DS ;
Cimprich, KA ;
Taya, Y ;
Tamai, K ;
Sakaguchi, K ;
Appella, E ;
Kastan, MB ;
Siliciano, JD .
SCIENCE, 1998, 281 (5383) :1677-1679
[6]  
CASEY G, 1991, ONCOGENE, V6, P1791
[7]   REGULATION OF TRANSCRIPTION FUNCTIONS OF THE P53 TUMOR-SUPPRESSOR BY THE MDM-2 ONCOGENE [J].
CHEN, JD ;
LIN, JY ;
LEVINE, AJ .
MOLECULAR MEDICINE, 1995, 1 (02) :142-152
[8]  
Chen JD, 1996, MOL CELL BIOL, V16, P2445
[9]   MAPPING OF THE P53 AND MDM-2 INTERACTION DOMAINS [J].
CHEN, JD ;
MARECHAL, V ;
LEVINE, AJ .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (07) :4107-4114
[10]   Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage [J].
Chen, LH ;
Agrawal, S ;
Zhou, WQ ;
Zhang, RW ;
Chen, JD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (01) :195-200