title: Impaired skin and mammary gland development and increased gamma-irradiation-induced tumorigenesis in mice carrying a mutation of S1152-ATM phosphorylation site in Brca1.
abstract: 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 Brca1-Delta11 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.
authors.affiliation: Radiation Medicine Branch, National Cancer Center, Goyang, Korea. sangsookim@ncc.re.kr
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Baek
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Kwan Ho
authors.initials: KH
authors.lastname: Cho
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005720:Gamma Rays; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011833:Radiation Injuries, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000254:growth & development* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases