| First Author | Kim SS | Year | 2006 |
| Journal | Mol Cell Biol | Volume | 26 |
| Issue | 18 | Pages | 6983-92 |
| PubMed ID | 16943438 | Mgi Jnum | J:112308 |
| Mgi Id | MGI:3656097 | Doi | 10.1128/MCB.00796-06 |
| Citation | Kim SS, et al. (2006) Hyperplasia and spontaneous tumor development in the gynecologic system in mice lacking the BRCA1-Delta11 isoform. Mol Cell Biol 26(18):6983-92 |
| abstractText | 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. Mutation analysis using gene targeting to create null mutations or disrupt BRCA-FL has provided much of our understanding of BRCA1 functions; however, targeted mutation of specific short forms of BRCA1 has not been reported. 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. |
