Cellular protection mechanisms against extracellular heme - Heme-hemopexin, but not free heme, activates the N-terminal c-Jun kinase
Cellular protection mechanisms against extracellular heme - Heme-hemopexin, but not free heme, activates the N-terminal c-Jun kinase
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DOI：
10.1074/jbc.274.2.638
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发表时间：
1999-01-08
影响因子：
4.8
通讯作者：
Smith, A
中科院分区：
文献类型：
--
作者：
Eskew, JD;Vanacore, RM;Smith, A
血红素结合蛋白通过紧密结合血红素消除其有害作用并防止非特异性血红素摄取来保护缺乏血红素结合蛋白受体的细胞，而具有血红素结合蛋白受体的细胞在遇到血红素-血红素结合蛋白时经历一系列细胞事件。对血红素-血红素结合蛋白的生化反应取决于其细胞外浓度，范围从低水平的细胞生长刺激到血红素毒性水平的细胞存活。高浓度（2-10 μ M）而非低浓度（0.01-1 μ M）的血红素-血红素结合蛋白增加小鼠肝癌（Hepa）细胞的蛋白质羰基含量，尽管是短暂的。这是由于与血红素转运相关的事件，因为钴-原卟啉IX-血红素结合蛋白结合受体并激活信号通路而不需要四吡咯转运，不会增加羰基含量。N-末端c-Jun激酶（JNK）被2-10 μ M血红素-血红素结合蛋白快速激活，然而增加的细胞内血红素水平既没有毒性也没有凋亡。在暴露于10 μ M血红素-血红素结合蛋白24小时后，Hepa细胞变得对0.1-0.75 μ M血红素-血红素结合蛋白的生长刺激不敏感，但HO-1仍然对血红素-血红素结合蛋白的诱导有反应。由于游离血红素不诱导JNK，信号传导事件，如通过激活JNK的c-Jun磷酸化以及NF κ B的核转位，G（2）/M阻滞，由血红素-血红素结合蛋白产生的p53和细胞周期抑制剂p21（WAF 1/CIP 1/SDI 1）的表达增加似乎在血红素-血红素结合蛋白的细胞保护中是至关重要的。
Hemopexin protects cells lacking hemopexin receptors by tightly binding heme abrogating its deleterious effects and preventing nonspecific heme uptake, whereas cells with hemopexin receptors undergo a series of cellular events upon encountering heme-hemopexin. The biochemical responses to heme-hemopexin depend on its extracellular concentration and range from stimulation of cell growth at low levels to cell survival at otherwise toxic levels of heme. High (2-10 mu M) but not low (0.01-1 mu M) concentrations of heme-hemopexin increase, albeit transiently, the protein carbonyl content of mouse hepatoma (Hepa) cells. This is due to events associated with heme transport since cobalt-protoporphyrin IX-hemopexin, which binds to the receptor and activates signaling pathways without tetrapyrrole transport, does not increase carbonyl content. The N-terminal c-Jun kinase (JNK) is rapidly activated by 2-10 mu M heme-hemopexin, yet the increased intracellular heme levels are neither toxic nor apoptotic. After 24 h exposure to 10 mu M heme-hemopexin, Hepa cells become refractory to the growth stimulation seen with 0.1-0.75 mu M heme-hemopexin but HO-1 remains responsive to induction by heme-hemopexin, Since free heme does not induce JNK, the signaling events, like phosphorylation of c-Jun via activation of JNK as well as the nuclear translocation of NF kappa B, G(2)/M arrest, and increased expression of p53 and of the cell cycle inhibitor p21(WAF1/CIP1/SDI1) generated by heme-hemopexin appear to be of paramount importance in cellular protection by heme-hemopexin.