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

doi:10.1038/sj.onc.1203284

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 journal › Article › peer-review

54 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 language	English (US)
Pages (from-to)	6605-6614
Number of pages	10
Journal	Oncogene
Volume	18
Issue number	47
DOIs	https://doi.org/10.1038/sj.onc.1203284
State	Published - Nov 11 1999

Keywords

BRCA1
p14(ARF)
p53

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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@article{abcab3c9321c42639c64a49711f9cae7,

title = "BRCA1 signals ARF-dependent stabilization and coactivation of p53",

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.",

keywords = "BRCA1, p14(ARF), p53",

author = "Kumaravel Somasundaram and MacLachlan, {Timothy K.} and Burns, {Timothy F.} and Magda Sgag{\'i}as and Cowan, {Kenneth H.} and Weber, {Barbara L.} and El-Deiry, {Wafik S.}",

note = "Funding Information: The authors thank MF Roussel and CH Sherr for providing p19ARF7/7 mouse embryo fibroblasts. This work was supported in part by NIH Grant # CA7641701. WS El-Deiry is an Assistant Investigator of the Howard Hughes Medical Institute.",

year = "1999",

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doi = "10.1038/sj.onc.1203284",

language = "English (US)",

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journal = "Oncogene",

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AU - Somasundaram, Kumaravel

AU - MacLachlan, Timothy K.

AU - Burns, Timothy F.

AU - Sgagías, Magda

AU - Cowan, Kenneth H.

AU - Weber, Barbara L.

AU - El-Deiry, Wafik S.

N1 - Funding Information: The authors thank MF Roussel and CH Sherr for providing p19ARF7/7 mouse embryo fibroblasts. This work was supported in part by NIH Grant # CA7641701. WS El-Deiry is an Assistant Investigator of the Howard Hughes Medical Institute.

PY - 1999/11/11

Y1 - 1999/11/11

N2 - 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.

AB - 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.

KW - BRCA1

KW - p14(ARF)

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