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Molecular and Cellular Biology, June 2002, p. 4280-4292, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4280-4292.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

BRCA1 Directs a Selective p53-Dependent Transcriptional Response towards Growth Arrest and DNA Repair Targets

Timothy K. MacLachlan,1,2,{dagger} Rishu Takimoto,1,2,{ddagger} and Wafik S. El-Deiry1,2,3,4,5,6*

Laboratory of Molecular Oncology and Cell Cycle Regulation,1 Howard Hughes Medical Institute,2 Departments of Medicine,6 Genetics,3 Pharmacology,4 Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191045

Received 5 September 2001/ Returned for modification 8 October 2001/ Accepted 8 March 2002

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.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, University of Pennsylvania, Rm. 437, CRB, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-9015. Fax: (215) 573-9139. E-mail: wafik{at}mail.med.upenn.edu.

{dagger} Present address: CuraGen Corporation, Branford, CT 06405.

{ddagger} Present address: Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Molecular and Cellular Biology, June 2002, p. 4280-4292, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4280-4292.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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