Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells
Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells
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DOI：
10.1042/bj20091511
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发表时间：
2010-07-15
影响因子：
4.1
通讯作者：
Doi, Takefumi
中科院分区：
文献类型：
--
作者：
Ishimoto, Kenji;Tachibana, Keisuke;Doi, Takefumi
FDPS（法呢基二磷酸合成酶）催化法呢基二磷酸的形成，法呢基二磷酸是合成胆固醇和异戊二烯化细胞代谢物的关键中间体。FDPS也是含氮双膦酸盐的分子靶点，其在各种疾病中用作骨抗吸收药物。在本研究中，我们的特点是固醇反应元件和核因子Y（核因子Y）的结合位点在人类FDPS启动子。利用荧光素酶测定、电泳迁移率改变测定和染色质免疫沉淀测定，我们证明了这些元件负责FDPS基因的转录，并且其转录激活由SREBP-2（sterol-regulatory-element-binding protein 2）和NF-Y介导。我们还研究了甾醇介导的FDPS表达是否参与了由唑来膦酸（一种FDPS抑制剂）诱导的细胞增殖。我们发现，SREBP-2和NF-Y介导的FDPS基因转录调节调节细胞增殖。这些结果表明，SREBP-2和NF-Y是通过诱导FDPS表达来触发细胞增殖所必需的，并且唑来膦酸的药理学作用涉及该途径。
FDPS (farnesyl diphosphate synthase) catalyses the formation of farnesyl diphosphate, a key intermediate in the synthesis of cholesterol and isoprenylated cellular metabolites. FDPS is also the molecular target of nitrogen-containing bisphosphonates, which are used as bone-antiresorptive drugs in various disorders. In the present study, we characterized the sterol-response element and NF-Y (nuclear factor Y)-binding site in the human FDPS promoter. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that these elements are responsible for the transcription of the FDPS gene, and that its transcriptional activation is mediated by SREBP-2 (sterol-regulatory-element-binding protein 2) and NF-Y. We also investigated whether sterol-mediated FDPS expression is involved in the cell proliferation induced by zoledronic acid, an FDPS inhibitor. We show that the SREBP-2- and NF-Y-mediated regulation of FDPS gene transcription modulates cell proliferation. These results suggest that SREBP-2 and NF-Y are required to trigger cell proliferation through the induction of FDPS expression and that the pharmacological action of zoledronic acid is involved in this pathway.