Abstract

Mutation in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer. Recent studies have shown that the BRCA1 gene product may be important in mediating responses to DNA damage and genomic instability. Previous studies have indicated that overexpression of BRCA1 can induce apoptosis or cell cycle arrest at the G 2/M border in various cell types. Although the activation of JNK kinase has been implicated in BRCA1-induced apoptosis, the role of other members of the mitogen-activated protein kinase family in mediating the cellular response to BRCA1 has not yet been examined. In this study, we monitored the activities of three members of the MAPK family (ERK1/2, JNK, p38) in MCF-7 breast cancer cells and U2OS osteosarcoma cells after their exposure to a recombinant adenovirus expressing wild type BRCA1 (Ad.BRCA1). Overexpression of BRCA1 in MCF-7 cells resulted in arrest at the G 2/M border; however, BRCA1 expression in U2OS cells induced apoptosis. Although BRCA1 induced JNK activation in both cell lines, there were marked differences in ERK1/2 activation in response to BRCA1 expression in these two cell lines. BRCA1-induced apoptosis in U2OS cells was associated with no activation of ERK1/2. In contrast, BRCA1 expression in MCF-7 cells resulted in the activation of both ERK1/2 and JNK. To directly assess the role of ERK1/2 in determining the cellular response to BRCA1, we used dominant negative mutants of MEK1 as well as MEK1/2 inhibitor PD98059. Our results indicate that inhibition of ERK1/2 activation resulted in increased apoptosis after BRCA1 expression in MCF-7 cells. Furthermore, BRCA1-induced apoptosis involved activation of JNK, induction of Fas-L/Fas interaction, and activation of caspases 8 and 9. The studies presented in this report indicate that the response to BRCA1 expression is determined by the regulation of both the JNK and ERK1/2 signaling pathways in cells.

Original languageEnglish (US)
Pages (from-to)33422-33430
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number36
DOIs
StatePublished - Sep 6 2002

Fingerprint

Chemical activation
Apoptosis
MCF-7 Cells
Cells
BRCA1 Protein
MAP Kinase Kinase 4
Breast Neoplasms
BRCA1 Gene
Cell Line
Caspase 9
Caspase 8
MAP Kinase Signaling System
Genomic Instability
Osteosarcoma
Cell Cycle Checkpoints
Mitogen-Activated Protein Kinases
Adenoviridae
Ovarian Neoplasms
DNA Damage
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

BRCA1-induced apoptosis involves inactivation of ERK1/2 activities. / Yan, Ying; Haas, John P; Kim, Min; Sgagias, Magdalene K.; Cowan, Kenneth H.

In: Journal of Biological Chemistry, Vol. 277, No. 36, 06.09.2002, p. 33422-33430.

Research output: Contribution to journalArticle

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T1 - BRCA1-induced apoptosis involves inactivation of ERK1/2 activities

AU - Yan, Ying

AU - Haas, John P

AU - Kim, Min

AU - Sgagias, Magdalene K.

AU - Cowan, Kenneth H

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