The p53 response to DNA damage in vivo is independent of DNA-dependent protein kinase

被引:42
作者
Jhappan, C
Yusufzai, TM
Anderson, S
Anver, MR
Merlino, G
机构
[1] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA
[2] NCI, Pathol Histotechnol Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[3] NHGRI, Lab Gene Transfer, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1128/MCB.20.11.4075-4083.2000
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
Ionizing radiation (IR) exposure causes mammalian cells to undergo p53-dependent cell cycle arrest and/or apoptosis. The in vivo role of DNA-dependent protein kinase (DNA-PK) in the transduction of the DNA damage signal to p53 remains unresolved. To determine the relationship between DNA-PK and p53, we studied the cell cycle and apoptotic responses to IR in mice deficient in DNA-PK. Using the slip mouse, which harbors an inactivating mutation of the DNA-PK catalytic subunit (DNA-PKcs), we demonstrated not only that these DNA-PKcs null mutants were highly radiosensitive but also that upon IR treatment, p53 accumulated in their cultured cells and tissue. Induced p53 was transcriptionally active and mediated the induction of p21 and Bar in slip cells. Examination of the thymic cell cycle response to IR treatment indicated that the slip G(1)/S-phase cell cycle checkpoint function was intact. We further show that slip mice exhibited a higher level of spontaneous thymic apoptosis as well as a more robust apoptotic response to IR than wild-type mice. Together, these data demonstrate that the p53-mediated response to DNA damage is intact in cells devoid of DNA-PK activity and suggest that other kinases, such as the product of the gene (ATM) mutated in ataxia telangiectasia, are better candidates for regulating IR-induced phosphorylation and accumulation of p53.
引用
收藏
页码:4075 / 4083
页数:9
相关论文
共 48 条
  • [1] Anderson Carl W., 1992, Critical Reviews in Eukaryotic Gene Expression, V2, P283
  • [2] Araki R, 1999, CANCER RES, V59, P3543
  • [3] Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice
    Araki, R
    Fujimori, A
    Hamatani, K
    Mita, K
    Saito, T
    Mori, M
    Fukumura, R
    Morimyo, M
    Muto, M
    Itoh, M
    Tatsumi, K
    Abe, M
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (06) : 2438 - 2443
  • [4] Enhanced phosphorylation of p53 by ATN in response to DNA damage
    Banin, S
    Moyal, L
    Shieh, SY
    Taya, Y
    Anderson, CW
    Chessa, L
    Smorodinsky, NI
    Prives, C
    Reiss, Y
    Shiloh, Y
    Ziv, Y
    [J]. SCIENCE, 1998, 281 (5383) : 1674 - 1677
  • [5] Atm-deficient mice: A paradigm of ataxia telangiectasia
    Barlow, C
    Hirotsune, S
    Paylor, R
    Liyanage, M
    Eckhaus, M
    Collins, F
    Shiloh, Y
    Crawley, JN
    Ried, T
    Tagle, D
    WynshawBoris, A
    [J]. CELL, 1996, 86 (01) : 159 - 171
  • [6] 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
  • [7] Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse
    Blunt, T
    Gell, D
    Fox, M
    Taccioli, GE
    Lehmann, AR
    Jackson, SP
    Jeggo, PA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (19) : 10285 - 10290
  • [8] Analysis of variable (diversity) joining recombination in DNA-dependent protein kinase (DNA-PK)-deficient mice reveals DNA-PK-independent pathways for both signal and coding joint formation
    Bogue, MA
    Jhappan, C
    Roth, DB
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) : 15559 - 15564
  • [9] A SEVERE COMBINED IMMUNODEFICIENCY MUTATION IN THE MOUSE
    BOSMA, GC
    CUSTER, RP
    BOSMA, MJ
    [J]. NATURE, 1983, 301 (5900) : 527 - 530
  • [10] DNA-dependent protein kinase-independent activation of p53 in response to DNA damage
    Burma, S
    Kurimasa, A
    Xie, GF
    Taya, Y
    Araki, R
    Abe, M
    Crissman, HA
    Ouyang, H
    Li, GC
    Chen, DJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (24) : 17139 - 17143