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BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity.
- Source :
-
Science (New York, N.Y.) [Science] 2011 Oct 28; Vol. 334 (6055), pp. 525-8. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
BRCA1 Protein chemistry
Basic-Leucine Zipper Transcription Factors genetics
Basic-Leucine Zipper Transcription Factors metabolism
Cells, Cultured
Disease Models, Animal
Embryonic Stem Cells metabolism
Ligands
Mammary Neoplasms, Experimental metabolism
Mice
Mutant Proteins chemistry
Mutant Proteins genetics
Mutant Proteins metabolism
Pancreatic Neoplasms metabolism
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
RING Finger Domains
Tumor Suppressor Proteins chemistry
Tumor Suppressor Proteins metabolism
Ubiquitin-Protein Ligases chemistry
Ubiquitin-Protein Ligases metabolism
BRCA1 Protein metabolism
Genes, BRCA1
Mammary Neoplasms, Experimental genetics
Pancreatic Neoplasms genetics
Phosphoproteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 334
- Issue :
- 6055
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 22034435
- Full Text :
- https://doi.org/10.1126/science.1209909