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首页> 外文期刊>Journal of Cellular Physiology >Inactivation of Bcl-2 through IκB kinase (IKK)-dependent phosphorylation mediates apoptosis upon exposure to 4-hydroxynonenal (HNE)
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Inactivation of Bcl-2 through IκB kinase (IKK)-dependent phosphorylation mediates apoptosis upon exposure to 4-hydroxynonenal (HNE)

机译：失活的bcl - 2通过我κB激酶(IKK)端依赖磷酸化调节细胞凋亡在接触4-hydroxynonenal (HNE)

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Apoptosis of macrophage foam cells loaded with modified/oxidized lipids is implicated in destabilization of advanced atherosclerotic plaques in humans. Concentration of HNE, main aldehydic product of plasma LDL peroxidation, elevates in atherosclerotic lesions as well as in cultured cells under oxidative stress. Although this reactive aldehyde has been shown to promote apoptosis with the involvement of p38 MAPK and JNK in various mammalian cell lines, roles of B-cell lymphoma 2 (Bcl-2) family proteins remain to be deciphered. We demonstrated that HNE-induced apoptosis was accompanied by concurrent downregulations of antiapoptotic Bcl-x L and Mcl-1 as well as upregulation of proapoptotic Bak. Furthermore, phoshorylation of Bcl-2 at Thr56, Ser70, and probably more phosphorylation sites located on N-terminal loop domain associated with HNE-induced apoptosis in both U937 and HeLa cells while ectopic expression of a phospho-defective Bcl-2 mutant significantly attenuated apoptosis. In parallel to this, HNE treatment caused release of proapoptotic Bax from Bcl-2. Pharmacological inhbition of IKK inhibited HNE-induced Bcl-2 phosphorylation. Similarly, silencing IKKα and -β both ended up with abrogation of Bcl-2 phosphorylation along with attenuation of apoptosis. Moreover, both IKKα and -β coimmunoprecipitated with Bcl-2 and in vitro kinase assay proved the ability of IKK to phosphorylate Bcl-2. In view of these findings and considering HNE inhibits DNA-binding activity of nuclear factor-κB (NF-κB) through prevention of IκB phosphorylation/ubiquitination/proteolysis, IKK appears to directly interfere with Bcl-2 activity through phosphorylation in HNE-mediated apoptosis independent of NF-κB signaling.
机译：细胞凋亡的巨噬细胞含有泡沫细胞修改/氧化脂质有牵连不稳定先进的动脉粥样硬化人类的斑块。aldehydic血浆低密度脂蛋白过氧化反应的产物,提升在动脉粥样硬化病变培养细胞氧化应激。这种反应性醛促进细胞凋亡和p38 MAPK的参与物在不同哺乳动物细胞系的角色b细胞淋巴瘤2 (bcl - 2)家族蛋白质仍然存在破译。伴随着HNE-induced细胞凋亡并发downregulations凋亡Bcl-xL和mcl1 upregulationproapoptotic Bak。bcl - 2在Thr56 Ser70,可能更多磷酸化位点位于n端循环域与HNE-induced细胞凋亡有关U937和海拉细胞而异位表达显著的phospho-defective bcl - 2基因突变减毒细胞凋亡。治疗引起的释放proapoptotic伯灵顿bcl - 2。HNE-induced bcl - 2磷酸化。沉默IKKα和β两个了废除的bcl - 2磷酸化细胞凋亡的衰减。-βcoimmunoprecipitated bcl - 2和体外激酶试验证明IKK的能力使磷酸化bcl - 2。和考虑HNE抑制dna结合蛋白的活动核因子-κB (NF -κB)通过预防我κB磷酸化、泛素化、水解、IKK似乎直接干扰bcl - 2活动通过磷酸化HNE-mediated细胞凋亡NF -κB信号独立的。

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