title: Gamma-irradiation-induced DNA damage checkpoint activation involves feedback regulation between extracellular signal-regulated kinase 1/2 and BRCA1.
abstract: 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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.forename: Claudine P
authors.initials: CP
authors.lastname: Black
authors.forename: Phu T
authors.initials: PT
authors.lastname: Cao
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Haferbier
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Kolb
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Spieker
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Ristow
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Cowan
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology / Q000528:radiation effects; D025461:Feedback, Physiological / Q000528:radiation effects*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018816:Genes, cdc / Q000528:radiation effects*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3