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Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress

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Abstract

Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G2/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt-4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G2/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia.

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Acknowledgements

This work was supported in part by Uehara Memorial Foundation, Tamura Science and Technology Foundation, and Japanese Society for Thermal Medicine.

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Authors and Affiliations

  1. Department of Liberal Arts and Sciences, Toyama Prefectural University, Kurokawa 5180, Toyama, 939-0398, Japan

    Yukihiro Furusawa & Yuka Yamanouchi

  2. Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Yukihiro Furusawa, Takashi Iizumi, Qing-Li Zhao, Yohei Mitsuhashi & Takashi Kondo

  3. Proton Beam Therapy Center, Tsukuba University Hospital Radiation Oncology, Tsukuba, Japan

    Takashi Iizumi

  4. Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    Akinori Morita

  5. Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Atushi Enomoto

  6. Division of Molecular Genetic Research, Life Science Research Center, University of Toyama, Toyama, Japan

    Yoshiaki Tabuchi

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  1. Yukihiro Furusawa
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  2. Yuka Yamanouchi
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  3. Takashi Iizumi
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  9. Takashi Kondo
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Correspondence to Yukihiro Furusawa.

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Furusawa, Y., Yamanouchi, Y., Iizumi, T. et al. Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress. Apoptosis 22, 1225–1234 (2017). https://doi.org/10.1007/s10495-017-1402-2

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