Related Experiment Videos
BRCA1 is a selective co-activator of 14-3-3 sigma gene transcription in mouse embryonic stem cells
O Aprelikova1, A J Pace, B Fang
1Section of Molecular Signaling and Oncogenesis, Division of Clinical Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. apreliko@mail.nih.gov
Abstract:
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.
Insights
BRCA1 deficiency impairs gene expression, particularly affecting stress response and cell cycle control. Loss of BRCA1 impacts the 14-3-3 sigma gene, crucial for G2/M checkpoint arrest after radiation.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- BRCA1 is a tumor suppressor gene critical for breast and ovarian cancer prevention.
- Its roles in DNA repair and transcription are well-established.
- Understanding BRCA1's function in transcriptional regulation is key to cancer biology.
Purpose of the Study:
- To investigate the role of BRCA1 in transcriptional regulation.
- To analyze gene expression profiles in BRCA1-deficient mouse embryonic stem cells.
Main Methods:
- Microarray technology was employed to analyze gene expression profiles.
- Comparison of gene expression between BRCA1-deficient and wild-type cells.
Main Results:
- Loss of BRCA1 led to decreased expression of stress response, cytoskeleton, and protein metabolism genes.
- BRCA1 deficiency specifically down-regulated the p53 target gene 14-3-3 sigma.
- BRCA1-deficient cells failed to maintain G2/M growth arrest post-ionizing radiation exposure.
Conclusions:
- BRCA1 is essential for the proper transcriptional regulation of key cellular processes.
- BRCA1's induction of 14-3-3 sigma is p53-dependent and involves a p53 response element.
- BRCA1 deficiency compromises the G2/M checkpoint, impacting cellular response to DNA damage.