In the past year, we generated and analyzed a mouse model carrying a mutation that blocks the slicing between BRCA1 exons 10 and 11. Alternative splicing in the BRCA1 locus generates multiple protein products including BRCA1-Delta11, which is identical to the BRCA1 full-length isoform (BRCA1-FL) except for the absence of exon 11. To understand the physiologic functions of BRCA1-Delta11, we used a knock-in approach that blocks alternative splicing between exons 10 and 12 to prevent the formation of this form of BRCA1. We showed that homozygous mutant mice (Brca1(FL/FL)) were born at a Mendelian ratio without obvious developmental defects. However, the majority of Brca1(FL/FL) female mice showed mammary gland abnormalities and uterine hyperplasia after one year of age with spontaneous tumor formation. Cultured Brca1(FL/FL) cells exhibited abnormal centrosome amplification and reduction of G(1) population that was accompanied by accumulation of cyclin E and cyclin A. Accumulation of cyclin E was also found in epithelial layers of dilated ducts and hyperproliferative lobular regions in the mammary glands of Brca1(FL/FL) mice. These observations provide evidence that BRCA1 splicing variants are involved in BRCA1 functions in modulating G(1)/S transition, centrosome duplication, and repressing tumor formation. Thus, together with mutant mice generated earlier, we have generated and reported a total of five mutant models for BRCA1, including two null mutations, one conditional mutation, two isoform mutations and one point mutation. Our studies using these models demonstrate that BRCA1 plays essential functions in many biological processes, including transcription regulation, cell cycle progression, apoptosis, DNA damage repair, centrosome duplication and animal aging.

Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2011
Total Cost
$465,825
Indirect Cost
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Haigis, Marcia C; Deng, Chu-Xia; Finley, Lydia W S et al. (2012) SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 72:2468-72
Park, Seong-Hoon; Zhu, Yuming; Ozden, Ozkan et al. (2012) SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. Transl Cancer Res 1:15-21
Lee, M-H; Lahusen, T; Wang, R-H et al. (2012) Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 31:116-27
Xie, Yangli; Su, Nan; Jin, Min et al. (2012) Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. Hum Mol Genet 21:3941-55
Kim, Eun-Hee; Deng, Chuxia; Sporn, Michael B et al. (2012) CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev Res (Phila) 5:89-97
Chen, Guiqian; Deng, Chuxia; Li, Yi-Ping (2012) TGF-? and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8:272-88
Weng, Tujun; Yi, Lingxian; Huang, Junlan et al. (2012) Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. Arthritis Rheum 64:3982-92
Wang, Rui-Hong; Kim, Hyun-Seok; Xiao, Cuiying et al. (2011) Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 121:4477-90
Zhu, Min; Yi, Ming; Kim, Chang Hee et al. (2011) Integrated miRNA and mRNA expression profiling of mouse mammary tumor models identifies miRNA signatures associated with mammary tumor lineage. Genome Biol 12:R77
Zeng, Ni; Li, Yang; He, Lina et al. (2011) Adaptive basal phosphorylation of eIF2? is responsible for resistance to cellular stress-induced cell death in Pten-null hepatocytes. Mol Cancer Res 9:1708-17

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