BRCA1 Tumor Suppression Depends on BRCT Phosphoprotein Binding, But Not Its E3 Ligase Activity.
Summary of "BRCA1 Tumor Suppression Depends on BRCT Phosphoprotein Binding, But Not Its E3 Ligase Activity."
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.
Affiliation
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Journal Details
This article was published in the following journal.
Name: Science (New York, N.Y.)
ISSN: 1095-9203
Pages: 525-8
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22034435
- DOI: http://dx.doi.org/10.1126/science.1209909
Medical and Biotech [MESH] Definitions
Brca1 Protein
The phosphoprotein encoded by the BRCA1 gene (GENE, BRCA1). In normal cells the BRCA1 protein is localized in the nucleus, whereas in the majority of breast cancer cell lines and in malignant pleural effusions from breast cancer patients, it is localized mainly in the cytoplasm. (Science 1995;270(5237):713,789-91)
Genes, Brca1
A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 17 at locus 17q21. Mutations of this gene are associated with the formation of familial breast and ovarian cancer. It encodes a large, nuclear protein that is a component of DNA repair pathways.
Fanconi Anemia Complementation Group L Protein
An E3 UBIQUITIN LIGASE that plays a key role in the DNA damage response pathway of FANCONI ANEMIA PROTEINS. It is associated with mono-ubiquitination of FANCD2 PROTEIN and the redistribution of FANCD2 to nuclear foci containing BRCA1 PROTEIN.
Proto-oncogene Proteins C-mdm2
An E3 UBIQUITIN LIGASE that interacts with and inhibits TUMOR SUPPRESSOR PROTEIN P53. Its ability to ubiquitinate p53 is regulated by TUMOR SUPPRESSOR PROTEIN P14ARF.
F-box Proteins
A family of proteins that share the F-BOX MOTIF and are involved in protein-protein interactions. They play an important role in process of protein ubiquition by associating with a variety of substrates and then associating into SCF UBIQUITIN LIGASE complexes. They are held in the ubiquitin-ligase complex via binding to SKP DOMAIN PROTEINS.
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