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

Kenji Ishimoto, Keisuke Tachibana, Ikuko Hanano, Daisuke Yamasaki, Hiroki Nakamura, Megumi Kawai, Yasuomi Urano, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)347-357
Number of pages11
JournalBiochemical Journal
Volume429
Issue number2
DOIs
Publication statusPublished - 2010 Jul 15
Externally publishedYes

Keywords

  • Cell proliferation
  • Farnesyl diphosphate synthase (FDPS)
  • Nuclear factor Y(NF-Y)
  • Promoter
  • Sterol-regulatory-element-binding protein (SREBP)
  • Zoledronic acid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Ishimoto, K., Tachibana, K., Hanano, I., Yamasaki, D., Nakamura, H., Kawai, M., Urano, Y., Tanaka, T., Hamakubo, T., Sakai, J., Kodama, T., & Doi, T. (2010). Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells. Biochemical Journal, 429(2), 347-357. https://doi.org/10.1042/BJ20091511