Abstract
We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN·BRCA1(GEN)). We find that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues, and that human BRCA1 protein is expressed and stabilized following exposure to DNA damage. Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise lethal phenotype associated with the targeted hypomorphic allele (Brca1(ΔexIISA)). Brca1(-/-); TgN·BRCA1(GEN) bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fragment of chromosome 17 contains all elements necessary for the correct expression, localization, and function of the BRCA1 protein. Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4085-4090 |
| Number of pages | 6 |
| Journal | Oncogene |
| Volume | 19 |
| Issue number | 36 |
| DOIs | |
| State | Published - Aug 24 2000 |
Funding
The authors would like to thank Anne Harrington for the transgenic injections, Dr Chuxia Deng for the Brca1DexIISA mice, and Drs Cindy Wilson and Denis Slamon for antisera to human BRCA1. We would like to thank Drs L Iruela-Arispe, K Lyons and H Herschman, for comments on the manuscript. The authors are grateful for support from the Department of Defense Breast Cancer Initiative (DAMD 17-96-1-6095), the UCLA Human Gene Medicine Program, the UCLA Gyn. Oncology Program, and the Stop Cancer Foundation, to TF Lane. Also to the UK Medical Research Council (G9600577) to E Solomon and the Anti-Cancer Council of Victoria to MA Brown.
Keywords
- BRCA1
- Gene transfer
- Transgenic
- Tumor suppressor
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Cancer Research
