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Molecular and Cellular Biology, November 2004, p. 9498-9507, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9498-9507.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1

Sang Soo Kim,1 Liu Cao,1 Cuiling Li,1 Xiaoling Xu,1 L. Julie Huber,2 Lewis A. Chodosh,2 and Chu-Xia Deng1*

Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland,1 and Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania2

Received 22 March 2004/ Returned for modification 11 May 2004/ Accepted 4 August 2004

The tumor suppressor BRCA1 contains multiple functional domains that interact with many proteins. After DNA damage, BRCA1 is phosphorylated by CHK2 at serine 988, followed by a change in its intracellular location. To study the functions of CHK2-dependent phosphorylation of BRCA1, we generated a mouse model carrying the mutation S971A (S971 in mouse Brca1 corresponds to S988 in human BRCA1) by gene targeting. Brca1S971A/S971A mice were born at the expected ratio without a developmental defect, unlike previously reported Brca1 mutant mice. However, Brca1S971A/S971A mice suffered a moderately increased risk of spontaneous tumor formation, with a majority of females developing uterus hyperplasia and ovarian abnormalities by 2 years of age. After treatment with DNA-damaging agents, Brca1S971A/S971A mice exhibited several abnormalities, including increased body weight, abnormal hair growth pattern, lymphoma, mammary tumors, and endometrial tumors. In addition, the onset of tumor formation became accelerated, and 80% of the mutant mice had developed tumors by 1 year of age. We demonstrated that the Brca1S971A/S971A cells displayed reduced ability to activate the G2/M cell cycle checkpoint upon {gamma}-irradiation and to stabilize p53 following N-methyl-N'-nitro-N-nitrosoguanidine treatment. These observations suggest that Chk2 phosphorylation of S971 is involved in Brca1 function in modulating the DNA damage response and repressing tumor formation.

* Corresponding author. Mailing address: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10/9N105, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 402-7225. Fax: (301) 480-1135. E-mail: ChuxiaD{at}BDG10.NIDDK.NIH.gov.

Molecular and Cellular Biology, November 2004, p. 9498-9507, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9498-9507.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kim, S. S., Cao, L., Lim, S.-C., Li, C., Wang, R.-H., Xu, X., Bachelier, R., Deng, C.-X. (2006). Hyperplasia and Spontaneous Tumor Development in the Gynecologic System in Mice Lacking the BRCA1-{Delta}11 Isoform.. Mol. Cell. Biol. 26: 6983-6992 [Abstract] [Full Text]  
  • Deng, C.-X. (2006). BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res 34: 1416-1426 [Abstract] [Full Text]  
  • Kwak, E. L., Kim, S., Zhang, J., Cardiff, R. D., Schmidt, E. V., Haber, D. A. (2006). Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant. Cancer Res. 66: 1923-1928 [Abstract] [Full Text]  
  • Greenberg, R. A., Sobhian, B., Pathania, S., Cantor, S. B., Nakatani, Y., Livingston, D. M. (2006). Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev. 20: 34-46 [Abstract] [Full Text]  


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