γ-Irradiation-induced DNA damage checkpoint activation involves feedback regulation between extracellular signal-regulated Kinase 1/2 and BRCA1

Ying Yan, Claudine P. Black, Phu T. Cao, Jamie L. Haferbier, Ryan H. Kolb, Rebecca S. Spieker, Alexandra M. Ristow, Kenneth H Cowan

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Abstract

Previous studies from our laboratory have shown that the activation of G2-M checkpoint after exposure of MCF-7 breast cancer cells to γ-irradiation (IR) is dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Studies presented in this report indicate that IR exposure of MCF-7 cells is associated with a marked increase in expression of breast cancer 1 (BRCA1) tumor suppressor, an effect that requires ERK1/2 activation and involves posttranscriptional control mechanisms. Furthermore, reciprocal coimmunoprecipitation, as well as colocalization studies, indicate an interaction between BRCA1 and ERK1/2 in both nonirradiated and irradiated cells. Studies using short hairpin RNA targeting BRCA1 show that BRCA1 expression is necessary for IR-induced G2-M cell cycle arrest, as well as ERK1/2 activation in MCF-7 cells. Although BRCA1 expression is not required for IR-induced phosphorylation of ataxia telangiectasia mutated (ATM)-Ser1981, it is required for ATM-mediated downstream signaling events, including IR-induced phosphorylation of Chk2-Thr68 and p53-Ser20. Moreover, BRCA1 expression is also required for IR-induced ATM and rad3 related activation and Chk1 phosphorylation in MCF-7 cells. These results implicate an important interaction between BRCA1 and ERK1/2 in the regulation of cellular response after IR-induced DNA damage in MCF-7 cells.

Original languageEnglish (US)
Pages (from-to)5113-5121
Number of pages9
JournalCancer Research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
DNA Damage
Breast Neoplasms
MCF-7 Cells
Ataxia Telangiectasia
Phosphorylation
G2 Phase Cell Cycle Checkpoints
Small Interfering RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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γ-Irradiation-induced DNA damage checkpoint activation involves feedback regulation between extracellular signal-regulated Kinase 1/2 and BRCA1. / Yan, Ying; Black, Claudine P.; Cao, Phu T.; Haferbier, Jamie L.; Kolb, Ryan H.; Spieker, Rebecca S.; Ristow, Alexandra M.; Cowan, Kenneth H.

In: Cancer Research, Vol. 68, No. 13, 01.07.2008, p. 5113-5121.

Research output: Contribution to journalArticle

Yan, Ying ; Black, Claudine P. ; Cao, Phu T. ; Haferbier, Jamie L. ; Kolb, Ryan H. ; Spieker, Rebecca S. ; Ristow, Alexandra M. ; Cowan, Kenneth H. / γ-Irradiation-induced DNA damage checkpoint activation involves feedback regulation between extracellular signal-regulated Kinase 1/2 and BRCA1. In: Cancer Research. 2008 ; Vol. 68, No. 13. pp. 5113-5121.
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