BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets.
The pathway leading to BRCA1-dependent tumor suppression is not yet clear but appears to involve activities in DNA repair as well as gene transcription. Moreover, it has been shown that BRCA1 can regulate p53-dependent transcription. Because BRCA1 overexpression stabilizes wild-type p53 but does not lead to apoptosis of most cell lines, we investigated the selectivity of BRCA1 for p53-dependent target gene activation. We find that BRCA1-stabilized p53 regulates transcription of DNA repair and growth arrest genes while p53 stabilized by DNA-damaging agents induces a wide array of genes, including those involved in apoptosis. This differential expression profile was reflected in the treatment outcome--apoptosis following DNA damage and growth arrest after expression of BRCA1. Depletion of BRCA1 in wild-type-p53-expressing cells abolished the induction of such repair genes as p53R2, while the expression of PIG3, an apoptosis-inducing gene, was still induced. BRCA1 also conferred diminished cell death in a p53-dependent manner in response to adriamycin compared to that conferred by controls. These results suggest that BRCA1 selectively coactivates the p53 transcription factor towards genes that direct DNA repair and cell cycle arrest but not towards those that direct apoptosis.
MacLachlan
Timothy K
TK
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Takimoto
Rishu
R
El-Deiry
Wafik S
WS
D019313:BRCA1 Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D012264:Ribonucleotide Reductases / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C411296:TP53I3 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases