Glial cell line-derived neurotrophic factor up-regulates the expression of tyrosine hydroxylase gene in human neuroblastoma cell lines

J Neurochem. 2002 Aug;82(4):801-8. doi: 10.1046/j.1471-4159.2002.00993.x.


The role of glial cell line-derived neurotrophic factor (GDNF) in the survival of dopaminergic neurons has been well documented, but its effect on dopamine biosynthesis remains to be elucidated. In this study, the effect of GDNF on the gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis, was investigated. We found that GDNF elevated the expression of the TH gene at both mRNA and protein levels in TGW cells, a human neuroblastoma cell line. GDNF significantly enhances the transcription rate of the TH gene as actinomycin D prevented the induction of TH mRNA and GDNF increased the activity of the TH promoter. In addition, GDNF exerts a relatively weak but significant effect on the stability of TH mRNA, because GDNF delayed the degradation of TH mRNA and strengthened a special TH mRNA/protein interaction known to be relevant with TH mRNA stability. By comparing several human neurogenic cell lines, we found that GDNF-induced TH expression was only observed in the cells possessing Ret protein and coincided with the expression levels. Taken together, these results indicate that GDNF up-regulates the expression of the TH gene by promoting the transcription of the TH gene and the stability of TH mRNA with the Ret receptor dependency in some neuroblastoma cell lines. Thus, GDNF exerts its neurotrophic role not only in promoting cells survival, but also in affecting dopamine biosynthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Dactinomycin / pharmacology
  • Drosophila Proteins*
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Humans
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / pharmacology*
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • RNA Stability / drug effects
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Transcription, Genetic / drug effects
  • Tumor Cells, Cultured
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism*
  • Up-Regulation / drug effects


  • Drosophila Proteins
  • GDNF protein, human
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Dactinomycin
  • Tyrosine 3-Monooxygenase
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila