Regulation of tyrosine hydroxylase promoter activity by the von Hippel-Lindau tumor suppressor protein and hypoxia-inducible transcription factors

J Neurochem. 2003 Apr;85(2):483-91. doi: 10.1046/j.1471-4159.2003.01696.x.

Abstract

Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is induced by hypoxia in oxygen-sensitive cells of the carotid body and pheochromocytoma-derived PC12 cells. TH is also regulated by the von Hippel-Lindau tumor suppressor protein (pVHL). Here, we report that induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter. We also show that some of the effects of pVHL on activity of the TH promoter are mediated through HIFs. Low levels of pVHL are associated with decreased HIFalpha ubiquitination, increased accumulation of HIFalpha proteins, increased binding of HIFs to the HRE within the TH promoter, and increased activity of a TH promoter-reporter construct. In contrast, high levels of pVHL repress HIF accumulation and inhibit its activity in hypoxic cells. These results indicate that HIFs may play an important role in regulation of TH gene expression in oxygen-sensitive cells and also in the development of hypercatecholaminemia in pheochromocytoma tumors.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Hypoxia / physiology
  • Cell Nucleus / metabolism
  • Clone Cells
  • Gene Expression Regulation / physiology*
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ligases / genetics
  • Ligases / metabolism*
  • PC12 Cells
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology*
  • Rats
  • Response Elements / physiology
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins*
  • Tyrosine 3-Monooxygenase / genetics*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases*
  • Von Hippel-Lindau Tumor Suppressor Protein

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin
  • endothelial PAS domain-containing protein 1
  • Tyrosine 3-Monooxygenase
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ligases