Gamma-irradiation-induced DNA damage checkpoint activation involves feedback regulation between extracellular signal-regulated kinase 1/2 and BRCA1.
Previous studies from our laboratory have shown that the activation of G(2)-M checkpoint after exposure of MCF-7 breast cancer cells to gamma-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 G(2)-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.
Mesh Terms:
BRCA1 Protein, Cell Cycle Proteins, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Feedback, Physiological, Gamma Rays, Gene Expression Regulation, Neoplastic, Genes, cdc, Humans, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Models, Biological, Protein Binding, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Cells, Cultured, Tumor Suppressor Proteins
BRCA1 Protein, Cell Cycle Proteins, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Feedback, Physiological, Gamma Rays, Gene Expression Regulation, Neoplastic, Genes, cdc, Humans, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Models, Biological, Protein Binding, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Cells, Cultured, Tumor Suppressor Proteins
Cancer Res.
Date: Jul. 01, 2008
PubMed ID: 18593910
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- Interactions 4
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