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首页> 外文期刊>Cellular Signalling >ERK1 and ERK2 kinases activate hydroxyurea-induced S-phase checkpoint in MCF7 cells by mediating ATR activation
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ERK1 and ERK2 kinases activate hydroxyurea-induced S-phase checkpoint in MCF7 cells by mediating ATR activation

机译：ERK1和ERK2激酶通过介导ATR激活激活MCF7细胞中的羟基脲诱导的S期检查点

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摘要

Modulation of MEK has been demonstrated to affect hydroxyurea (HU) induced-DNA damage response (DDR), implying the involvement of ERK1 and ERK2 in the process. To directly examine how the ERK kinases function in HU-initiated DDR, we knocked-down either ERK1 or ERK2 in MCF7 cells. This resulted in reduction of HU-induced phosphorylation of CHK1 S345 (serine 345), p53 S15, and H2AX S139. While HU potently induced CDC2 Y15 (tyrosine 15) phosphorylation, an event causing CDC2 inactivation, inhibition of ERK kinases using U0126 (a MEK inhibitor), MEK1K97M (a dominant negative MEK1), and knockdown of either ERK1 or ERK2 significantly attenuated HU-induced CDC2 Y15 phosphorylation. As CDC2 kinase activity is required for mitosis, our observations reveal that ERK1 and ERK2 kinases play important roles in preventing mitotic entry in response to HU. Consistent with ATR being the apical kinase to initiate HU-induced DDR, knockdown of ERK1 or ERK2 significantly inhibited HU-induced ATR recruitment to the stalled replication forks (ATR foci), an event required for ATR activation. Mechanistically, knockdown of ERK1 or ERK2 resulted in relocation of ATR from the nucleoplasm to the nucleolus in response to HU, therefore making ATR unavailable to the sites of DNA damage. Taken together, we demonstrate that ERK kinases sit upstream of ATR to facilitate its activation.
机译：已经证明，MEK的调节会影响羟基脲（HU）诱导的DNA损伤反应（DDR），这意味着ERK1和ERK2参与了该过程。为了直接检查ERK激酶在HU启动的DDR中的功能，我们敲低了MCF7细胞中的ERK1或ERK2。这导致HU诱导的CHK1 S345（丝氨酸345），p53 S15和H2AX S139的磷酸化降低。 HU会强力诱导CDC2 Y15（酪氨酸15）磷酸化，这会导致CDC2失活，使用U0126（MEK抑制剂），ERK1K​​97M（占主导地位的阴性MEK1）抑制ERK激酶，以及敲低ERK1或ERK2都会大大减弱HU诱导的水平。 CDC2 Y15磷酸化。由于CDC2激酶活性是有丝分裂所必需的，因此我们的观察结果表明，ERK1和ERK2激酶在预防HU对有丝分裂进入中起重要作用。与ATR是引发HU诱导的DDR的顶端激酶一致，ERK1或ERK2的敲低显着抑制了HU诱导的ATR向停滞的复制叉（ATR灶）募集，这是ATR激活所需的事件。从机制上讲，敲除ERK1或ERK2会导致ATR在响应HU的过程中从核质转移到核仁，因此使ATR无法用于DNA损伤位点。两者合计，我们证明ERK激酶位于ATR的上游，以促进其激活。

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