BRCA1 signals ARF-dependent stabilization and coactivation of p53

Kumaravel Somasundaram, Timothy K. MacLachlan, Timothy F. Burns, Magda Sgagías, Kenneth H. Cowan, Barbara L. Weber, Wafik S. El-Deiry

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The hereditary breast and ovarian tumor suppressor BRCA1 can activate p53-dependent gene expression. We show here that BRCA1 increases p53 protein levels through a post-transcriptional mechanism. BRCA1-stabilized p53 has increased sequence-specific DNA-binding and transcriptional activity. BRCA1 does not stabilize p53 in p14(ARF)-deficient cells. A deletion mutant of BRCA1 which inhibits p53-dependent transcription confers resistance to topoisomerase II-targeted chemotherapy. Our results suggest that BRCA1 may trigger the p53 pathway through two potentially separate mechanisms: accumulation of p53 through a direct or indirect induction of p14(ARF) as well as direct transcriptional coactivation of p53. BRCA1 may also enhance chemosensitivity and repair of DNA damage through binding to and coactivation of p53.

Original languageEnglish (US)
Pages (from-to)6605-6614
Number of pages10
JournalOncogene
Volume18
Issue number47
DOIs
Publication statusPublished - Nov 11 1999

    Fingerprint

Keywords

  • BRCA1
  • p14(ARF)
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Somasundaram, K., MacLachlan, T. K., Burns, T. F., Sgagías, M., Cowan, K. H., Weber, B. L., & El-Deiry, W. S. (1999). BRCA1 signals ARF-dependent stabilization and coactivation of p53. Oncogene, 18(47), 6605-6614. https://doi.org/10.1038/sj.onc.1203284