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| Subject Categories: Cell Cycle | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 2167–2177, doi:10.1038/sj.emboj.7601115 Published online 4 May 2006 |
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| ATM–Chk2–p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency |
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| Liu Cao1, 5, Sangsoo Kim1, 5, Cuiying Xiao1, Rui-Hong Wang1, Xavier Coumoul1, Xiaoyan Wang1, Wen Mei Li1, Xiao Ling Xu1, Joseph A De Soto1, Hiroyuki Takai2, Sabine Mai4, Stephen J Elledge3, Noboru Motoyama2 and Chu-Xia Deng1 |
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1 Genetics of Development and Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA 2 Department of Geriatric Research, National Institute for Longevity Sciences, Morioka, Obu, Japan 3 Department of Genetics, Harvard Medical School, Boston, MA, USA 4 Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada To whom correspondence should be addressed Chu-Xia Deng, Genetics of Development & Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10/9N105, Bethesda, MD 20892, USA. Tel.: +1 301 402 7225; Fax: +1 301 480 1135; E-mail: chuxiad@bdg10.niddk.nih.gov 5 These authors contributed equally to this work Received 13 September 2005; Accepted 4 April 2006; Published online 4 May 2006. |
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| Abstract |
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BRCA1 is a checkpoint and DNA damage repair gene that secures genome integrity. We have previously shown that mice lacking full-length Brca1 (Brca1 11/11) die during embryonic development. Haploid loss of p53 completely rescues embryonic lethality, and adult Brca111/11p53+/- mice display cancer susceptibility and premature aging. Here, we show that reduced expression and/or the absence of Chk2 allow Brca111/11 mice to escape from embryonic lethality. Compared to Brca111/11p53+/- mice, lifespan of Brca111/11Chk2-/- mice was remarkably extended. Analysis of Brca111/11Chk2-/- mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca111/11Chk2-/- female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM–Chk2–p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer. |
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| Keywords: aging, apoptosis, breast cancer, cell senescence, G1/S cell cycle checkpoint |
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