A Possible Mechanism for Hyperthermic Radiosensitization Mediated through Hyperthermic Lability of Ku Subunits in DNA-Dependent Protein Kinase

Matsumoto, Yoshihisa; Suzuki, Norio; Sakai, Kazuo; Morimatsu, Akeshi; Hirano, Kazuya; Murofushi, Hiromu

doi:10.1006/bbrc.1997.6689

Cited by 50 publications

(22 citation statements)

References 27 publications

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“…Moreover, another possible mechanism of radiosensitization by hyperthermia has been suggested to involve the hyperthermic instability of the Ku subunits of DNA-PK, which contribute to the repair of radiation-induced doublestrand breaks in DNA. 7,8) Patients with tumors that have p53 mutations often have a worse prognosis than those with tumors that have wild-type p53 (wtp53). 9) For prognosispredictive assays of cancer therapy, the genetic status of the p53 gene is the most important candidate among various cancer-related genes.…”

Section: Introductionmentioning

confidence: 99%

The Role of p53 Molecule in Radiation and Hyperthermic Therapies

Yasumoto

Takahashi

Ohnishi

et al. 2003

JOURNAL OF HEALTH SCIENCE

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Section: Introductionmentioning

confidence: 99%

The Role of p53 Molecule in Radiation and Hyperthermic Therapies

Yasumoto

Takahashi

Ohnishi

et al. 2003

JOURNAL OF HEALTH SCIENCE

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“…This implicates DNA-PK in the thermal radiosensitization phenomenon. Ku protein may be intrinsically heat-labile (23,24), in which case heat treatment may reduce double strand break repair. An alternative possibility is that binding of DNA-PK to HSF1 in heat-treated cells competes with its ability to interact with the DNA repair machinery.…”

mentioning

confidence: 99%

DNA-dependent Protein Kinase Protects against Heat-induced Apoptosis

Nueda¹,

Hudson

Mivechi

et al. 1999

Journal of Biological Chemistry

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Purified heat shock transcription factor 1 (HSF1) binds to both the regulatory and catalytic components of the DNA-dependent protein kinase (DNA-PK). This observation suggests that DNA-PK may have a physiological role in the heat shock response. To investigate this possibility, we performed a comparison of cell lines that were deficient in either the Ku protein or the DNA-PK catalytic subunit versus the same cell lines that had been rescued by the introduction of a functional gene. DNA-PK-negative cell lines were up to 10-fold more sensitive to heat-induced apoptosis than matched DNA-PK-positive cell lines. There may be a regulatory interaction between DNA-PK and HSF1 in vivo, because constitutive overexpression of HSF1 sensitized the DNA-PK-positive cells to heat but had no effect in DNA-PK-negative cells. The initial burst of hsp70 mRNA expression was similar in DNA-PK-negative and -positive cell lines, but the DNA-PK-negative cells showed an attenuated rate of mRNA synthesis at later times and, in some cases, lower heat shock protein expression. These findings provide evidence for an antiapoptotic function of DNA-PK that is experimentally separable from its mechanical role in DNA double strand break repair.The DNA-dependent protein kinase (DNA-PK) 1 is composed of a 470-kDa catalytic subunit (DNA-PKcs) and a 70/80-kDa heterodimeric regulatory component known as Ku protein. Ku protein binds avidly to DNA ends (1) and recruits DNA-PKcs to form an active complex (2-4). Mutations in DNA-PKcs or Ku protein have been described in mammals, flies, and yeast, and in each case, the mutant organism is deficient in double strand break repair, sensitive to ionizing radiation, or both (reviewed in Refs. 5 and 6). Binding of DNA-PK components to DNA is believed to be the first step in a repair pathway that involves a number of other gene products (reviewed in Ref. 7).It is not clear if the ability of DNA-PK to protect against the cytotoxic effect of ionizing radiation is attributable solely to the mechanical role of the enzyme in DNA repair or whether DNA-PK also participates in antiapoptotic signaling. There have been several reports that DNA-PK physically interacts with signaling molecules, including poly(A)DP-ribose polymerase, IB, Vav, c-Abl, and certain transcription factors (8 -12), but the physiological significance of these interactions has not yet been fully explored.In the present study, we investigate the in vivo role of a previously described interaction between DNA-PK and the heat shock transcription factor, HSF1 (12, 13). These prior studies have shown that purified HSF1 binds to both the Ku protein and DNA-PKcs (13). The binding requires a phylogenetically conserved region of HSF1 that includes amino acids 203-280 and results in a stimulation of DNA-PK phosphorylation activity of up to 20-fold in an in vitro reaction (13). These observations suggest that DNA-PK may be involved in regulating some aspect of the heat shock response in vivo.Other evidence also suggests an involvement of DNA-PK in the response to ...

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“…We reported the possible important roles of SAPK/JNK pathway (1), cleavage phenomenon of XRCC4 protein (2), characterization of the DNA-dependent protein kinase (DNA-PK) of MOLT-4 cells. The properties of MOLT-4 DNA-PK was normal and comparable to those described and purified from other cells, and was not considered the cause of its highly radiosensitive cell death (3).…”

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confidence: 64%