Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage.
Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage.
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Lyn 酪氨酸激酶作为应激激活蛋白激酶活性调节剂的作用，以响应 DNA 损伤。
DOI：
10.1128/mcb.20.15.5370-5380.2000
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发表时间：
2000
影响因子：
5.3
通讯作者：
Kufe,D
中科院分区：
文献类型：
--
作者：
Yoshida,K;Weichselbaum,R;Kharbanda,S;Kufe,D
细胞对DNA损伤的反应包括核林恩蛋白酪氨酸激酶的激活。使用缺乏林恩表达的细胞，目前的研究表明，林恩是诱导应激活化蛋白激酶（SAPK）对1-β-d-阿拉伯呋喃糖基胞嘧啶（ara-C）和其他遗传毒性物质的反应所必需的。相比之下，暴露于阿糖胞苷，电离辐射，或顺铂的细胞外信号调节蛋白激酶或p38丝裂原活化蛋白激酶的激活没有影响的Lyn-deficient细胞。在稳定表达激酶失活、显性阴性林恩（K-R）突变体的细胞中也获得了类似的结果。共表达研究表明，林恩，而不是林恩（K-R），诱导SAPK活性。此外，结果表明，林恩通过MKK 7依赖性、SEK 1非依赖性机制激活SAPK。由于MEKK 1在MKK 7和SAPK的上游发挥作用，显性负性MEKK 1（K-M）突变体阻断Lyn-induced SAPK活性的发现支持MEKK 1 → MKK 7通路的参与。结果还表明，抑制Lyn-induced SAPK活性消除了细胞对遗传毒性应激的凋亡反应。这些发现表明DNA损伤导致的SAPK活化部分由林恩介导，并且林恩→ MEKK 1 → MKK 7 →SAPK通路在遗传毒性剂诱导细胞凋亡中起作用。
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.