Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival

J Biol Chem. 2005 Jul 8;280(27):25571-9. doi: 10.1074/jbc.M501920200. Epub 2005 May 3.

Abstract

Fibroblast growth factor-1 (FGF-1) is highly expressed in motor neurons and can be released in response to sublethal cell injury. Because FGF-1 potently activates astroglia and exerts a direct neuroprotection after spinal cord injury or axotomy, we examined whether it regulated the expression of inducible and cytoprotective heme oxygenase-1 (HO-1) enzyme in astrocytes. FGF-1 induced the expression of HO-1 in cultured rat spinal cord astrocytes, which was dependent on FGF receptor activation and prevented by cycloheximide. FGF-1 also induced Nrf2 mRNA and protein levels and prompted its nuclear translocation. HO-1 induction was abolished by transfection of astrocytes with a dominant-negative mutant Nrf2, indicating that FGF-1 regulates HO-1 expression through Nrf2. FGF-1 also modified the expression of other antioxidant genes regulated by Nrf2. Both Nrf2 and HO-1 levels were increased and co-localized with reactive astrocytes in the degenerating lumbar spinal cord of rats expressing the amyotrophic lateral sclerosis-linked SOD1 G93A mutation. Overexpression of Nrf2 in astrocytes increased survival of co-cultured embryonic motor neurons and prevented motor neuron apoptosis mediated by nerve growth factor through p75 neurotrophin receptor. Taken together, these results emphasize the key role of astrocytes in determining motor neuron fate in amyotrophic lateral sclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects*
  • Astrocytes / enzymology
  • Cell Communication / physiology
  • Cell Survival / physiology
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Fibroblast Growth Factor 1 / pharmacology*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase-1
  • Humans
  • Membrane Proteins
  • Motor Neurons / cytology
  • NF-E2-Related Factor 2
  • Nerve Degeneration / metabolism
  • Rats
  • Rats, Mutant Strains
  • Rats, Sprague-Dawley
  • Spinal Cord / cytology*
  • Superoxide Dismutase / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nfe2l2 protein, rat
  • Trans-Activators
  • Fibroblast Growth Factor 1
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • SOD1 G93A protein
  • Superoxide Dismutase