Tumor Suppressor p53 Is Required To Modulate BRCA1 Expression

Abstract

Individuals carrying mutations in BRCA1 orp53 genes are predisposed to a variety of cancers, and both tumor suppressor genes have been implicated in DNA damage response pathways. We have analyzed a possible functional link betweenp53 and BRCA1 genes. Here we show that BRCA1 expression levels are down-regulated in response to p53 induction in cells that undergo either growth arrest, senescence, or apoptosis. Physiological stimuli, such as exposure to DNA-damaging agents, also result in negative regulation of BRCA1 levels in a p53-dependent manner prior to causing cell cycle arrest. Nuclear run-on experiments and luciferase reporter assays demonstrate that the changes in BRCA1 expression are mainly due to transcriptional repression induced by p53. In conclusion, the data show that BRCA1 expression levels are controlled by the presence and activity of wild-type p53 and suggest the existence of an intracellular p53/BRCA1 pathway in the response of cells to stress conditions.

ACKNOWLEDGMENTS

We thank A. M. Borras, J. R. Garreau, J. Licht, J. Manfredi, C. L. Reimer, and H. Zhang for helpful comments and discussion.

This work was supported by NIH grants CA78356, P50CA68425, P01CA80058, and CA79892.

ADDENDUM IN PROOF

W. S. El-Deiry's group has obtained results similar to those presented in this paper, and we thank them for communicating their data before publication (J. Biol. Chem., in press).