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ATM regulates target switching to escalating doses of radiation in the intestines

Nature Medicine volume 11, pages 484–490 (2005)Cite this article

A Corrigendum to this article was published on 01 February 2006

Abstract

Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase–mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm−/− mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm−/− mouse, reordering ceramide synthase–mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.

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Figure 1: Radiation induces an apoptotic response in the intestinal crypt clonogen compartment of mice exposed to ≥17 Gy WBR.
Figure 2: Exposure to 18 Gy WBR induces ceramide synthase–mediated apoptosis in the crypt clonogen compartment and crypt depletion, inhibited by FB1.
Figure 3: ATM depletion hypersensitizes intestinal crypt clonogens to radiation-induced ceramide synthase–mediated apoptosis.
Figure 4: Pharmacologic inactivation of ATM by antisense ODN hypersensitizes wild-type C57Bl/6 mice to WBR through ceramide synthase–mediated intestinal damage.
Figure 5: Dose response curves for ASMase-mediated endothelial apoptosis in the lamina propria of C57BL/6 mice and ceramide synthase–mediated apoptosis of crypt clonogens in wild-type C57BL/6 and Atm−/− mice after exposure to WBR.

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Acknowledgements

We thank M. Jaio for technical assistance. These studies were supported by US National Institutes of Health grants CA52462 (to Z.F.) and CA 85704 (to R.K.)

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Author notes

  1. Hui-Ju Ch'ang and Jerzy G Maj: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Hui-Ju Ch'ang, Jerzy G Maj, Jean-Philip Truman, Adriana Haimovitz-Friedman & Zvi Fuks

  2. Division of Cancer Research, National Health Research Institutes and Department of Onoclogy, National Taiwan University Hospital, Taipei, Taiwan

    Hui-Ju Ch'ang

  3. Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    François Paris, H Rosie Xing, Jianjun Zhang & Richard Kolesnick

  4. Inserm Unit 463, Institut de Biologie, 9 quai Moncousu, Nantes, 44093, Cedex 01, France

    François Paris

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Carlos Cardon-Cardo

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Supplementary information

Supplementary Fig. 1

Ceramide is generated in the GI mucosa of bFGF-treated C57Bl/6 mice after 18Gy but not 15Gy WBR. (PDF 212 kb)

Supplementary Fig. 2

Ionizing radiation hypersensitizes Atm−/− mice towards the lethal effects of WBR. (PDF 249 kb)

Supplementary Fig. 3

FB1 inhibits ceramide elevation in the proximal jejunal mucosa of Atm−/− mice. (PDF 248 kb)

Supplementary Fig. 4

ATM-AS-ODN decreases crypt survival at 3.5 days in C57Bl/6 mice exposed to 10Gy WBR. (PDF 208 kb)

Supplementary Methods (PDF 53 kb)

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Ch'ang, HJ., Maj, J., Paris, F. et al. ATM regulates target switching to escalating doses of radiation in the intestines. Nat Med 11, 484–490 (2005). https://doi.org/10.1038/nm1237

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