Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayed kinetics relative to wild-type p53

被引:30
作者
Stähler, F [1 ]
Roemer, K [1 ]
机构
[1] Univ Saarlandes, Sch Med, Dept Virol, D-66421 Homburg, Germany
关键词
cell death; p53; c-Myc; serine protease;
D O I
10.1038/sj.onc.1202245
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 (wt) p53 frequently induces apoptosis when expressed in tumor cells whereas mutant p53 acts as an oncoprotein and consequently, stimulates cell proliferation. We report here exceptions to that rule, p53 conformational mutant 175H and DNA contact mutant 273H provoke apoptosis in human p53-deficient Hep3B hepatoma cells with delayed kinetics relative to wt p53. Similarly, c-Myc strongly stimulates apoptosis in these cells. In contrast,, viral oncoproteins EIA and E7, and the cellular oncoprotein MDM-2, fail to elicit cytocidal responses. Efficient apoptotic cell death by mutant p53 requires oligomerization as 175H and 273H with deletions between amino acid residues 326 and 347 of the oligomerization domain are nontoxic. Apoptosis by mutant or wt p53 was significantly inhibited by the serine protease inhibitor AEBSF but not by the inactive analog AEBSA, Together, these results suggest that a nit p53-independent control mechanism is operational in Hep3B cells that eliminates cells upon sensing illegitimate proliferation signals originating from certain oncoproteins, including mutant p53 and Myc. We suggest that some tumor cell types lack p53 altogether because they tolerate neither wild-type nor mutant forms of the protein.
引用
收藏
页码:3507 / 3512
页数:6
相关论文
共 29 条
  • [1] 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
    ALLDAY, MJ
    INMAN, GJ
    CRAWFORD, DH
    FARRELL, PJ
    [J]. EMBO JOURNAL, 1995, 14 (20) : 4994 - 5005
  • [2] Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways
    Barlow, C
    Brown, KD
    Deng, CX
    Tagle, DA
    WynshawBoris, A
    [J]. NATURE GENETICS, 1997, 17 (04) : 453 - 456
  • [3] p53 in signaling checkpoint arrest or apoptosis
    Bates, S
    Vousden, KH
    [J]. CURRENT OPINION IN GENETICS & DEVELOPMENT, 1996, 6 (01) : 12 - 18
  • [4] INDUCTION OF THE GROWTH INHIBITOR IGF-BINDING PROTEIN-3 BY P53
    BUCKBINDER, L
    TALBOTT, R
    VELASCOMIGUEL, S
    TAKENAKA, I
    FAHA, B
    SEIZINGER, BR
    KLEY, N
    [J]. NATURE, 1995, 377 (6550) : 646 - 649
  • [5] P53-DEPENDENT APOPTOSIS IN THE ABSENCE OF TRANSCRIPTIONAL ACTIVATION OF P53-TARGET GENES
    CAELLES, C
    HELMBERG, A
    KARIN, M
    [J]. NATURE, 1994, 370 (6486) : 220 - 223
  • [6] Activation of CPP32 and Mch3 alpha in wild-type p53-induced apoptosis
    Chandler, JM
    Alnemri, ES
    Cohen, GM
    MacFarlane, M
    [J]. BIOCHEMICAL JOURNAL, 1997, 322 : 19 - 23
  • [7] p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells
    Chen, XB
    Ko, LJ
    Jayaraman, L
    Prives, C
    [J]. GENES & DEVELOPMENT, 1996, 10 (19) : 2438 - 2451
  • [8] WILD-TYPE P53 MEDIATES APOPTOSIS BY E1A, WHICH IS INHIBITED BY E1B
    DEBBAS, M
    WHITE, E
    [J]. GENES & DEVELOPMENT, 1993, 7 (04) : 546 - 554
  • [9] Friedlander P, 1996, MOL CELL BIOL, V16, P4961
  • [10] Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells
    Friedman, SL
    Shaulian, E
    Littlewood, T
    Resnitzky, D
    Oren, M
    [J]. ONCOGENE, 1997, 15 (01) : 63 - 70