Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1
Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1
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DOI：
10.1016/j.bbrc.2013.01.093
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发表时间：
2013-03-01
影响因子：
3.1
通讯作者：
Fujita, Jun
中科院分区：
文献类型：
--
作者：
Liu, Yu;Higashitsuji, Hiroaki;Fujita, Jun
Gankyrin（也称为p28或PSMD 10）是一种通常在肝细胞癌中过表达的癌蛋白。它由7个锚蛋白重复序列组成，并与多种蛋白质包括Rb、Cdk 4、MDM 2和NF-κ B相互作用。为了评估体内致癌活性，我们生产了在肝细胞中特异性过表达gankyrin的转基因小鼠。出乎意料的是，7只过表达B病毒X蛋白（HBX）启动子驱动的Gankyrin的F2转基因小鼠中有5只，3只过表达血清淀粉样蛋白P组分（SAP）启动子驱动的Gankyrin的创始小鼠中有1只发生了肝血管肿瘤（血管瘤/血管瘤），而野生型小鼠中没有一只发生。二乙基亚硝胺处理的转基因小鼠的肝脏内皮细胞过度生长比野生型小鼠更频繁。小鼠肝癌Hepa 1 -6细胞过度表达gankyrin形成的肿瘤比亲本Hepa 1 -6细胞在移植的小鼠皮肤中具有更多的血管。我们发现Gankyrin结合并隔离抑制缺氧诱导因子-1（FIH-1）的因子，这导致FIH-1和缺氧诱导因子-1 α（HIF-1 α）之间的相互作用减少，并且HIF-1促进VEGF产生的活性增加。Gankyrin在3%O-2条件下的作用比1%O-2和20%O-2条件下的作用更显著。因此，本研究澄清，至少部分地，血管肿瘤发生的机制，并建议Gankyrin可能发挥生理作用，在缺氧反应除了作为一种癌蛋白的作用。(C)2013 Elsevier Inc. All rights reserved.
Gankyrin (also called p28 or PSMD10) is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It consists of 7 ankyrin repeats and interacts with multiple proteins including Rb, Cdk4, MDM2 and NF-kappa B. To assess the oncogenic activity in vivo, we produced transgenic mice that overexpress gankyrin specifically in the hepatocytes. Unexpectedly, 5 of 7 F2 transgenic mice overexpressing hepatitis B virus X protein (HBX) promoter-driven gankyrin, and one of 3 founder mice overexpressing serum amyloid P component (SAP) promoter-driven gankyrin developed hepatic vascular neoplasms (hemangioma/hemangiosarcomas) whereas none of the wild-type mice did. Endothelial overgrowth was more frequent in the livers of diethylnitrosamine-treated transgenic mice than wild-type mice. Mouse hepatoma Hepa1-6 cells overexpressing gankyrin formed tumors with more vascularity than parental Hepa1-6 cells in the transplanted mouse skin. We found that gankyrin binds to and sequester factor inhibiting hypoxia-inducible factor-1 (FIH-1), which results in decreased interaction between FIH-1 and hypoxia-inducible factor-1 alpha (HIF-1 alpha) and increased activity of HIF-1 to promote VEGF production. The effects of gankyrin were more prominent under 3% O-2 than 1% or 20% O-2 conditions. Thus, the present study clarified, at least partly, mechanisms of vascular tumorigenesis, and suggests that gankyrin might play a physiological role in hypoxic responses besides its roles as an oncoprotein. (C) 2013 Elsevier Inc. All rights reserved.