BRCA1 is a selective co-activator of 14-3-3 sigma gene transcription in mouse embryonic stem cells.
BRCA1 gene is a tumor suppressor for breast and ovarian cancers with the putative role in DNA repair and transcription. To characterize the role of BRCA1 in transcriptional regulation, we analyzed gene expression profiles of mouse embryonic stem cells deficient in BRCA1 using microarray technology. We found that loss of BRCA1 correlated with decreased expression of several groups of genes including stress response genes, cytoskeleton genes, and genes involved in protein synthesis and degradation. Previous study showed that BRCA1 is a transcriptional co-activator of p53 protein; however the majority of p53 target genes remained at the same expression levels in BRCA1 knockout cells as in the wild type cells. The only p53 target gene down-regulated with the loss of BRCA1 was 14-3-3 sigma, a major G(2)/M checkpoint control gene. Similar to cells with decreased 14-3-3 sigma activity, BRCA1-deficient cells were unable to sustain G(2)/M growth arrest after exposure to ionizing radiation. We find that BRCA1 induction of 14-3-3 sigma requires the presence of wild type p53 and can be regulated by a minimal p53 response element.
Aprelikova
O
O
Section of Molecular Signaling and Oncogenesis, Division of Clinical Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. apreliko@mail.nih.gov
Pace
A J
AJ
Fang
B
B
Koller
B H
BH
Liu
E T
ET
D048948:14-3-3 Proteins; D000818:Animals; D014408:Biomarkers, Tumor; D005092:Exonucleases; D005095:Exoribonucleases; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D019398:Genes, BRCA1; D016158:Genes, p53; D051379:Mice; D009363:Neoplasm Proteins; D011506:Proteins / Q000235:genetics*; D013234:Stem Cells / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D011506:Proteins; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human