Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells.
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.
Ishimoto
Kenji
K
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Tachibana
Keisuke
K
Hanano
Ikuko
I
Yamasaki
Daisuke
D
Nakamura
Hiroki
H
Kawai
Megumi
M
Urano
Yasuomi
Y
Tanaka
Toshiya
T
Hamakubo
Takao
T
Sakai
Juro
J
Kodama
Tatsuhiko
T
Doi
Takefumi
T
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D023081:CCAAT-Binding Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D051228:Geranyltranstransferase / Q000096:biosynthesis / Q000235:genetics*; D018197:Hepatoblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D023081:CCAAT-Binding Factor; D017931:DNA Primers; D004273:DNA, Neoplasm; D004164:Diphosphonates; D007093:Imidazoles; D034741:RNA, Small Interfering; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; C402244:nuclear factor Y; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase