p53 dynamics vary between tissues and are linked with radiation sensitivity

被引:49
|
作者
Stewart-Ornstein, Jacob [1 ,2 ,6 ]
Iwamoto, Yoshiko [3 ]
Miller, Miles A. [3 ]
Prytyskach, Mark A. [3 ]
Ferretti, Stephane [4 ]
Holzer, Philipp [4 ]
Kallen, Joerg [4 ]
Furet, Pascal [4 ]
Jambhekar, Ashwini [1 ,2 ]
Forrester, William C. [5 ]
Weissleder, Ralph [1 ,2 ,3 ]
Lahav, Galit [1 ,2 ]
机构
[1] Harvard Med Sch, Blavatnik Inst, Dept Syst Biol, Boston, MA 02115 USA
[2] Harvard Med Sch, Blavatnik Inst, Ludwig Ctr Harvard, Boston, MA 02115 USA
[3] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA
[4] Novartis Inst Biomed Res, Basel, Switzerland
[5] Novartis Inst Biomed Res, Chem Biol & Therapeut, Cambridge, MA USA
[6] Univ Pittsburgh, Med Sch, Dept Computat & Syst Biol, Pittsburgh, PA USA
关键词
D O I
10.1038/s41467-021-21145-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies. p53 mediates the response to irradiation, however, tissues with similar levels of p53 have different radiation sensitivities. Here, the authors show that the in vivo p53 dynamics varies in these tissues after radiation, and the use of Mdm2 inhibitor to sustain p53 activity enhances radiosensitivity.
引用
收藏
页数:11
相关论文
共 50 条
  • [21] p53 and γ radiation in the normal breast
    Liu, Yajing
    Appleyard, M. Virginia C. L.
    Coates, Phillip J.
    Thompson, Alastair M.
    INTERNATIONAL JOURNAL OF RADIATION BIOLOGY, 2009, 85 (11) : 1026 - 1031
  • [22] Ovarian cancer linked to p53 gene
    Mayor, S
    BMJ-BRITISH MEDICAL JOURNAL, 1997, 315 (7100): : 77 - 77
  • [23] Comparable radiation sensitivity in p53 wild-type and p53 deficient tumor cells associated with different cell death modalities
    Ping Li
    Xiongxiong Liu
    Ting Zhao
    Feifei Li
    Qiqi Wang
    Pengcheng Zhang
    Ryoichi Hirayama
    Weiqiang Chen
    Xiaodong Jin
    Xiaogang Zheng
    Zhen Wang
    Qiang Li
    Cell Death Discovery, 7
  • [24] Abscopal effect of radiation therapy: Interplay between radiation dose and p53 status
    Strigari, Lidia
    Mancuso, Mariateresa
    Ubertini, Valentina
    Soriani, Antonella
    Giardullo, Paola
    Benassi, Marcello
    D'Alessio, Daniela
    Leonardi, Simona
    Soddu, Silvia
    Bossi, Gianluca
    INTERNATIONAL JOURNAL OF RADIATION BIOLOGY, 2014, 90 (03) : 248 - 255
  • [25] Comparable radiation sensitivity in p53 wild-type and p53 deficient tumor cells associated with different cell death modalities
    Li, Ping
    Liu, Xiongxiong
    Zhao, Ting
    Li, Feifei
    Wang, Qiqi
    Zhang, Pengcheng
    Hirayama, Ryoichi
    Chen, Weiqiang
    Jin, Xiaodong
    Zheng, Xiaogang
    Wang, Zhen
    Li, Qiang
    CELL DEATH DISCOVERY, 2021, 7 (01)
  • [26] Dynamics of Posttranslational Modifications of p53
    Fan, Qing-Duan
    Wu, Guang
    Liu, Zeng-Rong
    COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE, 2014, 2014
  • [27] The role of p53 in determining sensitivity to radiotherapy
    Gudkov, AV
    Komarova, EA
    NATURE REVIEWS CANCER, 2003, 3 (02) : 117 - 129
  • [28] The role of p53 in determining sensitivity to radiotherapy
    Andrei V. Gudkov
    Elena A. Komarova
    Nature Reviews Cancer, 2003, 3 : 117 - 129
  • [29] Modulation of transcriptional activity of p53 by ultraviolet radiation: Linkage between p53 pathway and DNA repair through damage recognition
    Zhu, QZ
    Wani, MA
    El-Mahdy, M
    Wani, C
    Wani, AA
    MOLECULAR CARCINOGENESIS, 2000, 28 (04) : 215 - 224
  • [30] Expression of p53β and Δ133p53 isoforms in different gastric tissues
    Ji, Wansheng
    Zhang, Na
    Zhang, Hongmei
    Ma, Jingrong
    Zhong, Hua
    Jiao, Jianxin
    Gao, Zhixing
    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2015, 8 (09): : 10468 - 10474