The oncoprotein gankyrin interacts with RelA and suppresses NF-kappaB activity.
The oncoprotein gankyrin interacts with RelA and suppresses NF-kappaB activity.
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发表时间：
2007
影响因子：
3.1
通讯作者：
H. Higashitsuji;H. Higashitsuji;Yu Liu;T. Masuda;Takanori Fujita;H. Abdel-Aziz;S. Kongkham;S. Dawson
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文献类型：
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作者：
H. Higashitsuji;H. Higashitsuji;Yu Liu;T. Masuda;Takanori Fujita;H. Abdel-Aziz;S. Kongkham;S. Dawson
甘氨酰蛋白是一种癌蛋白，通常在肝细胞癌中过度表达。它与多种蛋白质相互作用，加速肿瘤抑制基因Rb和P53的降解。由于gankyrin由7个ankyrin重复序列组成，并且在结构上与IkappaB相似，因此我们研究了它与NF-kappaB的相互作用。我们发现Gankyrin与relA直接结合。在HeLa和293细胞中，过表达gankyrin抑制了基础转录和TNFpha诱导的NF-kappaB的转录活性，而下调gankyrin则增加了它的转录活性。甘草蛋白不影响肿瘤坏死因子α诱导的细胞内核因子-kappaB DNA结合活性或RELA的核转位。抑制RELA核输出的Leptomycin B抑制了NF-kappaB的活性，而后者又被甘草苷进一步抑制。甘草蛋白的抑制作用被烟酰胺和组蛋白III型脱乙酰酶SIRT1下调所消除。因此，Gankyrin通过SIRT1调节乙酰化，与NF-kappaB结合并在转录水平上抑制其活性。
Gankyrin is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It interacts with multiple proteins and accelerates degradation of tumor suppressors Rb and p53. Since gankyrin consists of 7 ankyrin repeats and is structurally similar to IkappaBs, we investigated its interaction with NF-kappaB. We found that gankyrin directly binds to RelA. In HeLa and 293 cells, overexpression of gankyrin suppressed the basal as well as TNFalpha-induced transcriptional activity of NF-kappaB, whereas down-regulation of gankyrin increased it. Gankyrin did not affect the NF-kappaB DNA-binding activity or nuclear translocation of RelA induced by TNFalpha in these cells. Leptomycin B that inhibits nuclear export of RelA suppressed the NF-kappaB activity, which was further suppressed by gankyrin. The inhibitory effect of gankyrin was abrogated by nicotinamide as well as down-regulation of SIRT1, a class III histone deacetylase. Thus, gankyrin binds to NF-kappaB and suppresses its activity at the transcription level by modulating acetylation via SIRT1.