title: BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest.
abstract: 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.
authors.affiliation: Cancer Biology Program, Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Pat P
authors.initials: PP
authors.lastname: Ongusaha
authors.forename: Toru
authors.initials: T
authors.lastname: Ouchi
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Kim
authors.forename: Emily
authors.initials: E
authors.lastname: Nytko
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Kwak
authors.forename: Rosemary B
authors.initials: RB
authors.lastname: Duda
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53