PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis.
PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis.
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DOI：
10.1038/onc.2009.276
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发表时间：
2009-12-03
期刊：
影响因子：
8
通讯作者：
Magnuson, N. S.
中科院分区：
文献类型：
--
作者：
Gu, J. J.;Wang, Z.;Reeves, R.;Magnuson, N. S.
丝氨酸/苏氨酸激酶PIM1部分通过对促凋亡蛋白进行磷酸化修饰并抑制其活性，来促进细胞存活。凋亡信号调节激酶1（ASK1）是一种丝裂原活化蛋白激酶激酶激酶（MAPKKK），参与所谓的应激激活通路，该通路会引发细胞凋亡性死亡。在此我们发现，PIM1在体外和体内均可特异性地使ASK1丝氨酸残基83（Ser83）发生磷酸化，并且通过免疫共沉淀实验证实，PIM1在细胞内可与ASK1结合。利用H1299细胞进行的实验结果进一步表明，PIM1介导的ASK1磷酸化会降低由氧化应激诱导的ASK1激酶活性。PIM1使ASK1的Ser83磷酸化，可抑制ASK1介导的c-Jun氨基末端激酶（JNK）磷酸化以及p38激酶的磷酸化。在通常会导致细胞凋亡的过氧化氢（H2O2）诱导应激条件下，这些磷酸化事件与半胱天冬酶-3（caspase-3）激活受抑制相关，并可减少细胞死亡。此外，在H1299细胞中敲低PIM1会降低内源性ASK1的Ser83磷酸化水平，并且在H2O2处理后细胞活力下降。综上所述，这些数据揭示了PIM1促进细胞存活的一种新机制，即对应激激活激酶ASK1进行负调控。
The serine/threonine kinase, PIM1, is involved in promoting cell survival in part by phosphorylation and inhibition of proapoptotic proteins. ASK1, a mitogen-activated protein kinase kinase kinase (MAPKKK), is involved in the so-called stress-activated pathways that contribute to apoptotic cell death. Here we show that PIM1 phosphorylates ASK1 specifically on serine residue 83 (Ser83) both in vitro and in vivo and that PIM1 binds to ASK1 in cells by co-immunoprecipitation. Using H1299 cells, our results further demonstrate that PIM1 phosphorylation of ASK1 decreases its kinase activity induced by oxidative stress. PIM1 phosphorylation of ASK1 on Ser83 inhibited ASK1-mediated c-Jun N-terminal kinase (JNK) phosphorylation as well as phosphorylation of p38 kinase. Under H2O2-induced stress conditions that normally lead to apoptosis, these phosphorylation events were associated with inhibition of caspase-3 activation and resulted in reduced cell death. Moreover, knockdown of PIM1 in H1299 cells decreased phosphorylation of endogenous Ser83 of ASK1 and was associated with a decrease in cell viability after H2O2 treatment. Taken together, these data reveal a novel mechanism by which PIM1 promotes cell survival that involves negative regulation of the stress-activated kinase, ASK1.
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