ID 111999
Title Alternative
A radioprotective agonist for p53 transactivation
Author
Takahashi, Ippei Hiroshima University
Sasatani, Megumi Hiroshima University
Aoki, Shin Tokyo University of Science
Wang, Bing National Institutes for Quantum and Radiological Science and Technology
Ariyasu, Shinya Tokyo University of Science
Tanaka, Kaoru National Institutes for Quantum and Radiological Science and Technology
Yamaguchi, Tetsuji Hiroshima University
Sawa, Akiko Tokyo University of Science
Nishi, Yurie Tokyo University of Science
Teraoka, Tatsuro Tokyo University of Science
Ujita, Shohei Tokushima University
Kawate, Yosuke Tokushima University
Yanagawa, Chihiro Tokushima University
Tanimoto, Keiji Hiroshima University
Enomoto, Atsushi The University of Tokyo
Nenoi, Mitsuru National Institutes for Quantum and Radiological Science and Technology
Kamiya, Kenji Hiroshima University
Nagata, Yasushi Hiroshima University
Hosoi, Yoshio Hiroshima University|Tohoku University
Inaba, Toshiya Hiroshima University
Keywords
p53
p21
radioprotector
apoptosis
cell death
gastrointestinal syndrome
Content Type
Journal Article
Description
Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seems to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose-reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacological upregulation of radioprotective p53-target genes is an effective strategy for addressing the gastrointestinal syndrome.
Journal Title
Molecular Cancer Therapeutics
ISSN
15357163
15388514
NCID
AA11481959
AA12005007
Publisher
The American Association for Cancer Research, Inc.
Volume
17
Issue
2
Start Page
432
End Page
442
Published Date
2018-02
Rights
©2017 American Association for Cancer Research.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Author
departments
Medical Sciences