國家衛生研究院 NHRI:Item 3990099045/2701
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    题名: ATM regulates target switching to escalating doses of radiation in the intestines
    作者: Ch'ang, HJ;Maj, JG;Paris, F;Xing, HR;Zhang, JJ;Truman, JP;Cardon-Cardo, C;Haimovitz-Friedman, A;Kolesnick, R;Fuks, Z
    贡献者: National Institute of Cancer Research
    摘要: 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.
    关键词: Biochemistry & Molecular Biology;Cell Biology;Medicine, Research & Experimental
    日期: 2005-05
    關聯: Nature Medicine. 2005 May;11(5):484-490.
    Link to: http://dx.doi.org/10.1038/nm1237
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-8956&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000228915000019
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=21044450491
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