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
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 9 December 2011" - "CODEN: SCIEA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Maria Jasin
    223 Jasin
  2. Francesca Cole
    10 Cole