Genomic instability and apoptosis are frequent in p53 deficient young mice

被引:135
作者
Fukasawa, K
Wiener, F
VandeWoude, GF
Mai, SB
机构
[1] MANITOBA CANC TREATMENT & RES FDN, MANITOBA INST CELL BIOL, WINNIPEG, MB R3E 0V9, CANADA
[2] UNIV MANITOBA, DEPT PHYSIOL, WINNIPEG, MB R3E 0V9, CANADA
[3] NCI, FREDERICK CANC RES & DEV CTR, ABL BASIC RES PROGRAM, FREDERICK, MD 21702 USA
[4] UNIV CINCINNATI, COLL MED, DEPT CELL BIOL NEUROBIOL & ANAT, CINCINNATI, OH USA
[5] KAROLINSKA INST, CTR MICROBIOL & TUMOR BIOL, S-17177 STOCKHOLM, SWEDEN
关键词
p53; genomic instability; gene amplification; centrosome; Myc; apoptosis;
D O I
10.1038/sj.onc.1201482
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
The loss of p53 tumor suppressor functions results in genetic instability, characteristically associated with changes in chromosome ploidy and gene amplification. In vivo, we find that cells from various organs of 4 to 6-week old p53-nullizygous (p53 (-/-)) mice display aneuploidy and frequent gene amplification as well as evidence for apoptosis. Regardless of tissue types, many p53 (-/-) cells contain multiple centrosomes and abnormally formed mitotic spindles. Thus, chromosome vivo may be associated with abnormal Moreover, we observed a significant increase in the number of cells overexpressing c-Myc in p53 (-/-) mice. Consistent with previous studies showing that c-Myc overexpression is associated with gene amplification in vitro, many of the p53 (-/-) cells exhibited, in the same cell, c-Myc overexpression and amplified c-myc, dihydrofolate reductase (DHFR), and carbamoyl-phosphate synthetase-aspartate transcarbamoyl-dihydroorotase (CAD) genes. Furthermore, apoptosis was frequently observed in cells isolated from p53 (-/-) mice. The apoptotic cells contained abnormally amplified centrosomes, displayed aneuploidy, high levels of c-Myc expression, as web as gene amplification. These results indicate that a high number of aberrant cells is eliminated by p53-independent pathways in vivo.
引用
收藏
页码:1295 / 1302
页数:8
相关论文
共 49 条
  • [1] AMPLIFICATION OF CELLULAR ONCOGENES IN CANCER-CELLS
    ALITALO, K
    [J]. TRENDS IN BIOCHEMICAL SCIENCES, 1985, 10 (05) : 194 - 197
  • [2] MYC-MAX-MAD - A TRANSCRIPTION FACTOR NETWORK CONTROLLING CELL-CYCLE PROGRESSION, DIFFERENTIATION AND DEATH
    AMATI, B
    LAND, H
    [J]. CURRENT OPINION IN GENETICS & DEVELOPMENT, 1994, 4 (01) : 102 - 108
  • [3] CANCER - THE RISE OF THE GENETIC PARADIGM
    BISHOP, JM
    [J]. GENES & DEVELOPMENT, 1995, 9 (11) : 1309 - 1315
  • [4] BLYTH K, 1995, ONCOGENE, V10, P1717
  • [5] Myc versus USF: Discrimination at the cad gene is determined by core promoter elements
    Boyd, KE
    Farnham, PJ
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (05) : 2529 - 2537
  • [6] A P53-DEPENDENT MOUSE SPINDLE CHECKPOINT
    CROSS, SM
    SANCHEZ, CA
    MORGAN, CA
    SCHIMKE, MK
    RAMEL, S
    IDZERDA, RL
    RASKIND, WH
    REID, BJ
    [J]. SCIENCE, 1995, 267 (5202) : 1353 - 1356
  • [7] DENIS N, 1991, ONCOGENE, V6, P1453
  • [8] MICE DEFICIENT FOR P53 ARE DEVELOPMENTALLY NORMAL BUT SUSCEPTIBLE TO SPONTANEOUS TUMORS
    DONEHOWER, LA
    HARVEY, M
    SLAGLE, BL
    MCARTHUR, MJ
    MONTGOMERY, CA
    BUTEL, JS
    BRADLEY, A
    [J]. NATURE, 1992, 356 (6366) : 215 - 221
  • [9] INDUCTION OF APOPTOSIS IN FIBROBLASTS BY C-MYC PROTEIN
    EVAN, GI
    WYLLIE, AH
    GILBERT, CS
    LITTLEWOOD, TD
    LAND, H
    BROOKS, M
    WATERS, CM
    PENN, LZ
    HANCOCK, DC
    [J]. CELL, 1992, 69 (01) : 119 - 128
  • [10] ISOLATION OF MONOCLONAL-ANTIBODIES SPECIFIC FOR HUMAN C-MYC PROTO-ONCOGENE PRODUCT
    EVAN, GI
    LEWIS, GK
    RAMSAY, G
    BISHOP, JM
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1985, 5 (12) : 3610 - 3616