Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells

Biochem J. 2010 Jul 15;429(2):347-57. doi: 10.1042/BJ20091511.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites / genetics
  • Bone Density Conservation Agents / pharmacology
  • CCAAT-Binding Factor / antagonists & inhibitors
  • CCAAT-Binding Factor / genetics
  • CCAAT-Binding Factor / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Conserved Sequence
  • DNA Primers / genetics
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Diphosphonates / pharmacology
  • Gene Knockdown Techniques
  • Geranyltranstransferase / biosynthesis
  • Geranyltranstransferase / genetics*
  • Hepatoblastoma / genetics*
  • Hepatoblastoma / metabolism*
  • Hepatoblastoma / pathology
  • Humans
  • Imidazoles / pharmacology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • Sequence Homology, Nucleic Acid
  • Sterol Regulatory Element Binding Protein 2 / antagonists & inhibitors
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • Sterols / metabolism
  • Transcriptional Activation
  • Transfection
  • Zoledronic Acid


  • Bone Density Conservation Agents
  • CCAAT-Binding Factor
  • DNA Primers
  • DNA, Neoplasm
  • Diphosphonates
  • Imidazoles
  • RNA, Small Interfering
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • Sterols
  • nuclear factor Y
  • Zoledronic Acid
  • Geranyltranstransferase