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Regulation of tyrosine hydroxylase promoter activity by the von Hippel–Lindau tumor suppressor protein and hypoxia-inducible transcription factors
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.
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“Furthermore, hypoxia and HIFs are important regulators of the synthesis (Schnell et al., 2003) and secretion (Kumar et al., 1998) of catecholamines, which are key SNS neurotransmitters.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Schnell et al., 2003
Citations
Cites
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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“…transcription factors (HIFs). pVHL functions by recruiting target proteins to the complex for ubiquitination (Cockman et al. 2000; Kamura et al. 2000; Ohh et al. 2000) in a proline hydroxylation-dependent manner (Bruick and McKnight 2001; Ivan et al. 2001; Jaakkola et al. 2001; Yu et al. 2001).”
BackgroundHIF-1: mediator of physiological and pathophysiological responses to hypoxia
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Cited by
Sorted by citations
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687
“Furthermore, hypoxia and HIFs are important regulators of the synthesis (Schnell et al., 2003) and secretion (Kumar et al., 1998) of catecholamines, which are key SNS neurotransmitters.”
BackgroundComplex molecular regulation of tyrosine hydroxylase
Tekin, I., Roskoski, R., Carkaci-Salli, N., & Vrana, K. E. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1238-7 · Cited by 128
Tomak, A., Saglam-Metiner, P., Coban, R., Oksel-Karakus, C., & Yesil-Celiktas, O. (2025) · Tissue and Cell · doi:10.1016/j.tice.2025.103080 · Cited by 6
Metadata
- Authors
- Schnell, P. O., Ignacak, M. L., Bauer, A. L., Striet, J. B., Paulding, W. R., & Czyzyk‐Krzeska, M. F.
- Affiliations
- University of Cincinnati (US)
- Xavier University (US)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2003-04
- Volume
- 85
- Issue
- 2
- Pages
- 483-491
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2115377381
- Cited by
- 107
- References
- 3
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 7 · 2014: 4 · 2013: 2 · 2012: 4
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- VHL Alliance
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-66312, HL-58687, R01HL066312, T32HL07571, R01HL058687, T32HL007571)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- tyrosine hydroxylase, von Hippel-Lindau protein, hypoxia-inducible factor, hypoxia response element, promoter regulation, catecholamine synthesis, pheochromocytoma, carotid body, hypercatecholaminemia, transcriptional regulation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Cell Nucleus, Clone Cells, Gene Expression Regulation, Ligases, Promoter Regions, Genetic, Transcription Factors, Tyrosine 3-Monooxygenase, Cell Hypoxia, PC12 Cells, Response Elements, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Rats, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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- CoChat. (2026). Citation check: Regulation of tyrosine hydroxylase promoter activity by the von Hippel–Lindau tumor suppressor protein and hypoxia-inducible transcription factors. https://app.cochat.ai/papers/10.1046/j.1471-4159.2003.01696.x
- The paper
- Schnell, P. O., Ignacak, M. L., Bauer, A. L., Striet, J. B., Paulding, W. R., & Czyzyk‐Krzeska, M. F. (2003). Regulation of tyrosine hydroxylase promoter activity by the von Hippel–Lindau tumor suppressor protein and hypoxia-inducible transcription factors. Journal of Neurochemistry. https://doi.org/10.1046/j.1471-4159.2003.01696.x
