FGF induces a switch in death receptor pathways in neuronal cells

J Neurosci. 2001 Jul 15;21(14):4996-5006. doi: 10.1523/JNEUROSCI.21-14-04996.2001.

Abstract

Basic fibroblast growth factor (FGF2) has many roles in neuronal development and maintenance including effects on mitogenesis, survival, fate determination, differentiation, and migration. Using a conditionally immortalized rat hippocampal cell line, H19-7, and primary hippocampal cultures, we now demonstrate that FGF2 treatment differentially regulates members of the tumor necrosis factor (TNF) superfamily of death domain receptors and their ligands. H19-7 cells transferred from serum to defined (N2) medium undergo apoptosis by a Fas-dependent mechanism similar to primary neurons. In contrast, H19-7 cells treated with FGF undergo apoptosis by a Fas-independent mechanism. FGF suppresses the Fas death pathway but also induces apoptosis by activation of a TNFalpha death pathway in both H19-7 and hippocampal progenitor cells. Expression of the TNF receptor 1 (TNFR1) or TNFR2 in H19-7 cells is sufficient to sensitize the cells to TNFalpha, similar to the effects of FGF. Because TNFalpha can be either proapoptotic or antiapoptotic, these results provide an explanation for the divergent trophic effects of FGF2 treatment and the observation that multiple trophic inputs are required for the survival of specific neurons.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Apoptosis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Fas Ligand Protein
  • Fibroblast Growth Factor 2 / pharmacology*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Intracellular Signaling Peptides and Proteins*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Signal Transduction / drug effects*
  • Transfection
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / metabolism

Substances

  • Antigens, CD
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Caspase Inhibitors
  • Fas Ligand Protein
  • Faslg protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Fibroblast Growth Factor 2
  • Caspases