Proteasome Inhibition by Fellutamide B Induces Nerve Growth Factor Synthesis

John Hines, Michael Groll, Margaret Fahnestock, Craig M. Crews

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Neurotrophic small molecules have the potential to aid in the treatment of neuronal injury and neurodegenerative diseases. The natural product fellutamide B, originally isolated from Penicillium fellutanum, potently induces nerve growth factor (NGF) release from fibroblasts and glial-derived cells, although the mechanism for this neurotrophic activity has not been elucidated. Here, we report that fellutamide B potently inhibits proteasome catalytic activity. High-resolution structural information obtained from cocrystallization of the 20S proteasome reveals novel aspects regarding β-subunit binding and adduct formation by fellutamide B to inhibit their hydrolytic activity. We demonstrate that fellutamide B and other proteasome inhibitors increased NGF gene transcription via a cis-acting element (or elements) in the promoter. These results demonstrate an unrecognized connection between proteasome inhibition and NGF production, suggesting a possible new strategy in the development of neurotrophic agents.

Original languageEnglish
Pages (from-to)501-512
Number of pages12
JournalChemistry and Biology
Volume15
Issue number5
DOIs
StatePublished - 19 May 2008

Keywords

  • CHEMBIO
  • MOLNEURO
  • PROTEINS

Fingerprint

Dive into the research topics of 'Proteasome Inhibition by Fellutamide B Induces Nerve Growth Factor Synthesis'. Together they form a unique fingerprint.

Cite this