BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity Journal Article
| Authors: | Shakya, R.; Reid, L. J.; Reczek, C. R.; Cole, F.; Egli, D.; Lin, C. S.; DeRooij, D. G.; Hirsch, S.; Ravi, K.; Hicks, J. B.; Szabolcs, M.; Jasin, M.; Baer, R.; Ludwig, T. |
| Article Title: | BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity |
| Abstract: | Germline mutations of the breast cancer 1 (BRCA1) gene are a major cause of familial breast and ovarian cancer. The BRCA1 protein displays E3 ubiquitin ligase activity, and this enzymatic function is thought to be required for tumor suppression. To test this hypothesis, we generated mice that express an enzymatically defective Brca1. We found that this mutant Brca1 prevents tumor formation to the same degree as does wild-type Brca1 in three different genetically engineered mouse (GEM) models of cancer. In contrast, a mutation that ablates phosphoprotein recognition by the BRCA C terminus (BRCT) domains of BRCA1 elicits tumors in each of the three GEM models. Thus, BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression. |
| Keywords: | controlled study; gene mutation; mutation; nonhuman; pancreatic neoplasms; mutant protein; protein domain; mouse; animals; mice; cells, cultured; mus; breast cancer; gene expression; animal experiment; animal model; protein; protein binding; enzyme activity; brca1 protein; wild type; carcinogenesis; cancer inhibition; tumor suppressor gene; amino terminal sequence; protein multimerization; genetic engineering; genes, brca1; tumor suppressor proteins; phosphoproteins; ligands; embryonic stem cells; rodent; mutant proteins; tumor; disease models, animal; disease control; ubiquitin protein ligase e3; basic-leucine zipper transcription factors; biochemistry; ubiquitin-protein ligases; protein interaction domains and motifs; phosphoprotein; growth rate; mammary neoplasms, experimental; chemical binding; hypothesis testing; genetically modified organism; ring finger domains |
| Journal Title: | Science |
| Volume: | 334 |
| Issue: | 6055 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2011-10-28 |
| Start Page: | 525 |
| End Page: | 528 |
| Language: | English |
| DOI: | 10.1126/science.1209909 |
| PUBMED: | 22034435 |
| PROVIDER: | scopus |
| PMCID: | PMC3904783 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 9 December 2011" - "CODEN: SCIEA" - "Source: Scopus" |
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