DNA-DAMAGE IN HUMAN B-CELLS CAN INDUCE APOPTOSIS, PROCEEDING FROM G(1)/S WHEN P53 IS TRANSACTIVATION COMPETENT AND G(2)/M WHEN IT IS TRANSACTIVATION DEFECTIVE

被引:105
作者
ALLDAY, MJ
INMAN, GJ
CRAWFORD, DH
FARRELL, PJ
机构
[1] ST MARYS HOSP,SCH MED,LUDWIG INST CANC RES,LONDON W2 1PG,ENGLAND
[2] UNIV LONDON LONDON SCH HYG & TROP MED,DEPT CLIN SCI,LONDON WC1E 7HT,ENGLAND
关键词
APOPTOSIS; CELL CYCLE CHECKPOINTS; EPSTEIN-BARR VIRUS; P53;
D O I
10.1002/j.1460-2075.1995.tb00182.x
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
Cisplatin treatment of Epstein-Barr virus-immortalized human B lymphoblastoid cell lines (LCLs) results in p53-mediated apoptosis which occurs largely in a population of cells at the G(1)/S boundary of the cell cycle. Cell cycle progression appears to be required for this apoptosis because arresting cells earlier in G(1) inhibited apoptosis despite the accumulation of p53, Overexpression of wild-type p53 also induces apoptosis in an LCL. Therefore six mutant genes derived from Burkitt's lymphoma (BL) cells were assayed for their ability to induce apoptosis when similarly overexpressed. The same genes were analysed in transient transfection assays for their ability to transactivate appropriate reporter plasmids. A correlation between the ability of p53 to transactivate and induce apoptosis was revealed. The only mutant capable of transactivation also induced apoptosis. Further analysis of the BL lines in which p53 had been characterized showed that whereas some lines were essentially resistant to cisplatin, three were rapidly induced to undergo apoptosis. All three have a single p53 allele encoding a mutant which is incapable of transactivation or (for two tested) mediating apoptosis when expressed in an LCL. Cell cycle analysis revealed that this apparently p53-independent apoptosis did not follow G(1) arrest but in fact occurred largely in cells distributed in the G(2)/M phase of the cell cycle. These data suggest the existence of a second checkpoint in the G(2) or M phase which, in the absence of a functional p53, is the primary point of entry into the apoptosis programme following DNA damage.
引用
收藏
页码:4994 / 5005
页数:12
相关论文
共 61 条
  • [51] APOPTOSIS IN THE PATHOGENESIS AND TREATMENT OF DISEASE
    THOMPSON, CB
    [J]. SCIENCE, 1995, 267 (5203) : 1456 - 1462
  • [52] VOJTESEK B, 1992, J IMMUNOL METHODS, V151, P537
  • [53] BIOLOGICAL-ACTIVITIES OF P53 MUTANTS IN BURKITTS-LYMPHOMA CELLS
    VOUSDEN, KH
    CROOK, T
    FARRELL, PJ
    [J]. JOURNAL OF GENERAL VIROLOGY, 1993, 74 : 803 - 810
  • [54] THE P21 INHIBITOR OF CYCLIN-DEPENDENT KINASES CONTROLS DNA-REPLICATION BY INTERACTION WITH PCNA
    WAGA, S
    HANNON, GJ
    BEACH, D
    STILLMAN, B
    [J]. NATURE, 1994, 369 (6481) : 574 - 578
  • [55] MYC-MEDIATED APOPTOSIS REQUIRES WILD-TYPE P53 IN A MANNER INDEPENDENT OF CELL-CYCLE ARREST AND THE ABILITY OF P53 TO INDUCE P21(WAF1/CIP1)
    WAGNER, AJ
    KOKONTIS, JM
    HAY, N
    [J]. GENES & DEVELOPMENT, 1994, 8 (23) : 2817 - 2830
  • [56] TUMOR BIOLOGY - P53, GUARDIAN OF RB
    WHITE, E
    [J]. NATURE, 1994, 371 (6492) : 21 - 22
  • [57] P53 AND E2F-1 COOPERATE TO MEDIATE APOPTOSIS
    WU, XW
    LEVINE, AJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (09) : 3602 - 3606
  • [58] Wyllie A H, 1980, Int Rev Cytol, V68, P251
  • [59] BAD, A HETERODIMERIC PARTNER FOR BCL-X(L) AND BCL-2, DISPLACES BAX AND PROMOTES CELL-DEATH
    YANG, E
    ZHA, JP
    JOCKEL, J
    BOISE, LH
    THOMPSON, CB
    KORSMEYER, SJ
    [J]. CELL, 1995, 80 (02) : 285 - 291
  • [60] P53-MEDIATED CELL-DEATH - RELATIONSHIP TO CELL-CYCLE CONTROL
    YONISHROUACH, E
    GRUNWALD, D
    WILDER, S
    KIMCHI, A
    MAY, E
    LAWRENCE, JJ
    MAY, P
    OREN, M
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (03) : 1415 - 1423