期刊
CANCER RESEARCH
卷 69, 期 24, 页码 9291-9300出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-2418
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资金
- National Institute of Diabetes, Digestive, and Kidney Diseases. NIH (Bethesda, MD)
- National Cancer Center of Korea [NCC-0910020]
- Korea Healthcare Technology RD Project [A090095]
- National Research Foundation of Kore [2009-0070609]
- Korea Health Promotion Institute [A090095] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2009-0070609] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after gamma-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1(S1152A/S1152A) mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1(S1152A/S1152A) mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of gamma-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1(S1152A/S1152A) female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-alpha, such as Brcal-Delta 11 mutation. On low-dose gamma-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1(S1152A/S1152A) embryonic fibroblasts failed to accumulate p53 on gamma-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis. [Cancer Res 2009;69(24):9291-300]
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