BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest

• Published in: Oncogene Vol. 22; no. 24; pp. 3749 - 3758
• Main Authors: ONGUSAHA, Pat P, OUCHI, Toru, KIM, Kyung-Tae, NYTKO, Emily, KWAK, Jennifer C, DUDA, Rosemary B, DENG, Chu-Xia, LEE, Sam W
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 12.06.2003; Nature Publishing Group
• Subjects: Animals; Apoptosis; Biological and medical sciences; BRCA1 protein; BRCA1 Protein - physiology; Cancer; Cell cycle; Cell death; Cell Division; Cell Line; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA Damage; DNA microarrays; Embryo fibroblasts; Embryos; Fundamental and applied biological sciences. Psychology; Genes; Mice; Molecular and cellular biology; Oligonucleotide Array Sequence Analysis; p53 Protein; Phenotype; Phenotypes; Senescence; Temperature-sensitive mutant; Transcription; Tumor suppressor genes; Tumor Suppressor Protein p53 - physiology; Tumors; γ Radiation; United States > US; Senescence; TP53 Gene; Growth; DNA; DNA damage; BRCA1; Microarray; P53
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206439

The tumor suppressor protein BRCA1 has been shown to enhance p53 transcription, whereas activated p53 represses BRCA1 transcription. To further understand the functional interaction of these proteins, we investigated the role of BRCA1 in p53-induced phenotypes. We found that BRCA1 when subjected to forced expression acts synergistically with wild-type p53, resulting in irreversible growth arrest, as shown by VhD mouse fibroblast cells expressing a temperature-sensitive mutant of p53. Furthermore, reintroduction of both BRCA1 and p53 into BRCA1(-/-)/p53(-/-) mouse embryonic fibroblasts markedly increased the senescence phenotype compared to that induced by p53 alone. In particular, we found that BRCA1 expression attenuated p53-mediated cell death in response to gamma-irradiation. Moreover, microarray screening of 11 000 murine genes demonstrated that a set of genes upregulated by p53 is enhanced by coexpression of BRCA1 and p53, suggesting that BRCA1 and p53 exert a promoter selectivity leading to a specific phenotype. Taken together, our results provide evidence that BRCA1 is involved in p53-mediated growth suppression rather than apoptosis.