Inhibition of I κ B-α phosphorylation at serine and tyrosine acts independently on sensitization to DNA damaging agents in human glioma cells
Inhibition of I κ B-α phosphorylation at serine and tyrosine acts independently on sensitization to DNA damaging agents in human glioma cells
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DOI：
10.1054/bjoc.1999.0872
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发表时间：
1999-12
影响因子：
8.8
通讯作者：
Junji Miyakoshi;K. Yagi
中科院分区：
文献类型：
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作者：
Junji Miyakoshi;K. Yagi
在哺乳动物细胞中，控制细胞放射敏感性的分子机制和/或内在因素尚未完全了解。最近的研究表明，核因子κB（NF-κB）就是其中之一。NF-κB的活化和调节受NF-κB的细胞抑制蛋白IκB-α的严格控制。最重要的是，磷酸化调节抑制剂IκB-α的活性，该抑制剂将NF-κB隔离在胞质溶胶中。IκB-α的磷酸化有两种不同的途径，如丝氨酸（第32和36位残基）和酪氨酸（第42位残基）磷酸化。为了评估转录因子NF-κB在细胞对DNA损伤剂的敏感性中的作用，我们构建了三种不同类型的表达质粒，即S-IκB（在残基32和36处突变）、Y-IκB（在残基42处突变）和SY-IκB（在残基32、36和42处突变）。表达S-IκB和Y-IκB蛋白的细胞克隆与亲本细胞和载体转染细胞相比对X射线敏感。表达SY-IκB的细胞克隆具有更高的放射敏感性。经磷酸化抑制剂除草霉素A处理后，表达SY-IκB的细胞对X射线的敏感性没有改变，而表达S-IκB和Y-IκB的细胞及亲本细胞对X射线的敏感性增强。这些克隆对阿霉素和紫外线的敏感性变化与X射线敏感性变化非常相似。抑制IκB-α在丝氨酸和酪氨酸的磷酸化独立地对X射线、阿霉素和UV的增敏作用起作用。这些结果提示NF-κB诱导的转录激活可能在DNA损伤修复过程中发挥作用。目前的研究提出了一种可能性，即通过抑制丝氨酸和酪氨酸磷酸化来灭活NF-κB，这可能有助于癌症的放疗和化疗。2000癌症研究运动
Molecular mechanisms and/or intrinsic factors controlling cellular radiosensitivity are not fully understood in mammalian cells. The recent studies have suggested that nuclear factor κB (NF-κB) is one of such factors. The activation and regulation of NF-κB are tightly controlled by IκB-α, a cellular inhibitory protein of NF-κB. Most importantly, phosphorylation regulates activity of the inhibitor IκB-α, which sequesters NF-κB in the cytosol. Two different pathways for the phosphorylation of IκB-α are demonstrated, such as serine (at residues 32 and 36) and tyrosine (at residue 42) phosphorylations. To assess a role of the transcription factor, NF-κB, on cellular sensitivity to DNA damaging agents, we constructed three different types of expression plasmids, i.e. S-IκB (mutations at residues 32 and 36), Y-IκB (mutation at residue 42) and SY-IκB (mutations at residues 32, 36 and 42). The cell clones expressing S-IκB and Y-IκB proteins became sensitive to X-rays as compared with the parental and vector-transfected cells. The cell clones expressing SY-IκB were further radiosensitive. By the treatment with herbimycin A, an inhibitor of phosphorylation, the X-ray sensitivity of cells expressing SY-IκB did not change, while that of the cells expressing S-IκB and Y-IκB and the parental cells was enhanced. Change in the sensitivity to adriamycin and UV in those clones was very similar to that in the X-ray sensitivity. The inhibition of IκB-α phosphorylation at serine and tyrosine acts independently on the sensitization to X-rays, adriamycin and UV. These findings suggest that the transcriptional activation induced by NF-κB may play a role in the DNA damage repair. The present study proposes a possibility that the inactivation of NF-κB by inhibition of both serine and tyrosine phosphorylations may be useful for the treatment of cancer in radio- and chemotherapies. © 2000 Cancer Research Campaign