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首页> 外文期刊>Cellular Signalling >Both ERK1 and ERK2 kinases promote G2/M arrest in etoposide-treated MCF7 cells by facilitating ATM activation
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Both ERK1 and ERK2 kinases promote G2/M arrest in etoposide-treated MCF7 cells by facilitating ATM activation

机译：ERK1和ERK2激酶均通过促进ATM活化来促进依托泊苷处理的MCF7细胞中的G2 / M阻滞

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The MEK-ERK pathway plays a role in DNA damage response (DDR). This has been thoroughly studied by modulating MEK activation. However, much less has been done to directly examine the contributions of ERK1 and ERK2 kinases to DDR. Etoposide induces G2/M arrest in a variety of cell lines, including MCF7 cells. DNA damage-induced G2/M arrest depends on the activation of the protein kinase ataxia-telangiectasia mutated (ATM). ATM subsequently activates CHK2 by phosphorylating CHK2 threonine 68 (T68) and CHK2 inactivates CDC25C via phosphorylation of its serine 216 (S216), resulting in G2/M arrest. To determine the contribution of ERK1 and ERK2 to etoposide-induced G2/M arrest, we individually knocked-down ERK1 and ERK2 in MCF7 cells using specific small interfering RNA (siRNA). Knockdown of either kinases significantly reduced ATM activation in response to etoposide treatment, and thereby attenuated phosphorylation of the ATM substrates, including the S139 of H2AX (γH2AX), p53 S15, and CHK2 T68. Consistent with these observations, knockdown of either ERK1 or ERK2 reduced etoposide-induced CDC25C S216 phosphorylation and significantly compromised etoposide-induced G2/M arrest in MCF7 cells. Taken together, we demonstrated that both ERK1 and ERK2 kinases play a role in etoposide-induced G2/M arrest by facilitating activation of the ATM pathway. These observations suggest that a cellular threshold level of ERK kinase activity is required for the proper checkpoint activation in MCF7 cells.
机译：MEK-ERK途径在DNA损伤反应（DDR）中起作用。已通过调节MEK激活对此进行了深入研究。但是，直接检查ERK1和ERK2激酶对DDR的贡献还很少。依托泊苷在包括MCF7细胞在内的多种细胞系中诱导G2 / M阻滞。 DNA损伤诱导的G2 / M阻滞取决于蛋白激酶共济失调-毛细血管扩张突变（ATM）的激活。 ATM随后通过磷酸化CHK2苏氨酸68（T68）激活CHK2，CHK2通过其丝氨酸216的磷酸化使CDC25C失活（S216），导致G2 / M停滞。为了确定ERK1和ERK2对依托泊苷诱导的G2 / M阻滞的贡献，我们使用特定的小干扰RNA（siRNA）分别敲低了MCF7细胞中的ERK1和ERK2。两种激酶的敲低反应均显着降低了对依托泊苷治疗的响应，从而减弱了ATM底物的磷酸化，包括H2AX（SH139）（γH2AX），p53 S15和CHK2 T68。与这些观察结果一致，ERK1或ERK2的敲低减少了依托泊苷诱导的CDC25C S216磷酸化，并严重损害了依托泊苷诱导的MCF7细胞G2 / M阻滞。综上所述，我们证明了ERK1和ERK2激酶均通过促进ATM途径的活化在依托泊苷诱导的G2 / M阻滞中发挥作用。这些观察结果表明，MCF7细胞中适当的检查点激活需要ERK激酶活性的细胞阈值水平。

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