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PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation

R Deng ; J Tang ; J-G Ma ; S-P Chen ; L-P Xia ; W-J Zhou ; D-D Li ; G-K Feng ; Y-X Zeng ; X-F Zhu

Oncogene, 2010, Vol.30(8), p.944 [Periódico revisado por pares]

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  • Título:
    PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation
  • Autor: R Deng ; J Tang ; J-G Ma ; S-P Chen ; L-P Xia ; W-J Zhou ; D-D Li ; G-K Feng ; Y-X Zeng ; X-F Zhu
  • Assuntos: Cancer Cells -- Genetic Aspects ; Cancer Cells -- Control ; Cancer Cells -- Research ; Radiotherapy -- Health Aspects ; Dna Binding Proteins -- Physiological Aspects ; Dna Binding Proteins -- Genetic Aspects ; Dna Binding Proteins -- Research
  • É parte de: Oncogene, 2010, Vol.30(8), p.944
  • Descrição: An elevated DNA-repair capacity in cancer cells leads to radiation resistance and severely limits the efficacy of radiation therapy. Activation of Akt is tightly associated with resistance to radiotherapy, and Mre11 protein has important role during the repair of DNA double-strand breaks (DSBs). In this report, our results showed that inhibition of Akt activity impaired the repair of DSBs in CNE2 cells, whereas activated Akt promoted the repair of DSBs in HeLa cells. Knockdown of Mrell also impaired the process of DSB repair in both these two cell lines. More importantly, we found that Akt could regulate Mrell expression. Inhibition of Akt activity by small interfering RNA or LY294002 efficiently downregulated the Mrell expression in CNE2 cells, and transfection with myr-Akt plasmid in HeLa cells upregulated the Mrell expression. In addition, luciferase reporter analysis revealed that Mrell reporter activity increased after transfection with myr-Akt1 plasmids, and this myr-Akt1-induced transcriptional activity was blocked in the presence of LY294002. Further study showed GSK3[beta]/[beta]-catenin/LEF-l pathway was involved in this regulation. Knockdown of [beta]-catenin or LEF-1 led to the down-regulation of Mre11, whereas overexpression of [beta]-catenin led to upregulation of Mre11. The chromatin immunoprecipitation assay assay showed [beta]-catenin/LEF-1 heterodimer could directly bind to the promoter of Mre11 in vivo. And the luciferase activity of the pGL3-Mre11 and pGL3-Lef increased in HeLa cells following [beta]-catenin plasmid co-transfected, but was abolished when the LEF1-binding conserved sequences of Mre11 promoter were mutated. These results together support Akt can upregulate the expression of Mre11 through GSK3[beta]/[beta]-catenin/ LEF pathway to elevate DSB-repair capacity in cancer cells. Oncogene (2011) 30, 944-955; doi: 10.1038/onc.2010.467; published online 18 October 2010 Keywords: Akt; Mre11; DSB repair; ionizing radiation

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