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首页> 外文期刊>Molecular and Cellular Biology >Role for Lyn Tyrosine Kinase as a Regulator of Stress-Activated Protein Kinase Activity in Response to DNA Damage
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Role for Lyn Tyrosine Kinase as a Regulator of Stress-Activated Protein Kinase Activity in Response to DNA Damage

机译：Lyn酪氨酸激酶作为应激激活蛋白激酶活性调节剂对DNA损伤的调节作用

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The cellular response to DNA damage includes activation of the nuclear Lyn protein tyrosine kinase. Using cells deficient in Lyn expression, the present studies demonstrate that Lyn is required in part for induction of the stress-activated protein kinase (SAPK) in the response to 1-β-d-arabinofuranosylcytosine (ara-C) and other genotoxic agents. By contrast, exposure of Lyn-deficient cells to ara-C, ionizing radiation, or cisplatin had no effect on activation of extracellular signal-regulated protein kinase or p38 mitogen-activated protein kinase. Similar findings were obtained in cells stably expressing a kinase-inactive, dominant-negative Lyn(K-R) mutant. Coexpression studies demonstrate that Lyn, but not Lyn(K-R), induces SAPK activity. In addition, the results demonstrate that Lyn activates SAPK by an MKK7-dependent, SEK1-independent mechanism. As MEKK1 functions upstream to MKK7 and SAPK, the finding that a dominant-negative MEKK1(K-M) mutant blocks Lyn-induced SAPK activity supports involvement of the MEKK1→MKK7 pathway. The results also demonstrate that inhibition of Lyn-induced SAPK activity abrogates the apoptotic response of cells to genotoxic stress. These findings indicate that activation of SAPK by DNA damage is mediated in part by Lyn and that the Lyn→MEKK1→MKK7→SAPK pathway is functional in the induction of apoptosis by genotoxic agents.
机译：细胞对DNA损伤的反应包括核Lyn蛋白酪氨酸激酶的激活。使用缺乏Lyn表达的细胞，本研究表明，在对1-β-d-阿拉伯呋喃糖基胞嘧啶（ara-C）和其他遗传毒性剂的应答中，Lyn是诱导应激活化蛋白激酶（SAPK）的一部分。相比之下，Lyn缺陷细胞暴露于ara-C，电离辐射或顺铂对细胞外信号调节蛋白激酶或p38促丝裂原活化蛋白激酶的激活没有影响。在稳定表达激酶无活性，显性阴性Lyn（K-R）突变体的细胞中获得了类似的发现。共表达研究表明，Lyn（而不是Lyn（K-R））诱导SAPK活性。此外，结果表明，Lyn通过MKK7依赖性，SEK1依赖性机制激活SAPK。由于MEKK1在MKK7和SAPK的上游起作用，因此发现负显性MEKK1（K-M）突变体阻断Lyn诱导的SAPK活性支持了MEKK1→MKK7途径的参与。结果还表明，抑制Lyn诱导的SAPK活性可以消除细胞对遗传毒性应激的凋亡反应。这些发现表明，DNA损伤引起的SAPK活化部分地由Lyn介导，并且Lyn→MEKK1→MKK7→SAPK途径在遗传毒性剂诱导的细胞凋亡中起作用。

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