Regulation of tyrosine hydroxylase promoter activity by the von Hippel-Lindau tumor suppressor protein and hypoxia-inducible transcription factors.
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.
Schnell
Phillip O
PO
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Ignacak
Monika L
ML
Bauer
Amy L
AL
Striet
Justin B
JB
Paulding
Waltke R
WR
Czyzyk-Krzeska
Maria F
MF
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015687:Cell Hypoxia / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002999:Clone Cells; D005786:Gene Expression Regulation / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D051381:Rats; D020218:Response Elements / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014446:Tyrosine 3-Monooxygenase; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1