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Regulation of tyrosine hydroxylase promoter activity by the von Hippel–Lindau tumor suppressor protein and hypoxia‐inducible transcription factors
Author(s) -
Schnell Phillip O.,
Ignacak Monika L.,
Bauer Amy L.,
Striet Justin B.,
Paulding Waltke R.,
CzyzykKrzeska Maria F.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01696.x
Subject(s) - tyrosine hydroxylase , transcription factor , hypoxia inducible factors , transcription (linguistics) , biology , tyrosine , pheochromocytoma , tyrosine 3 monooxygenase , promoter , gene expression , microbiology and biotechnology , gene , endocrinology , enzyme , biochemistry , linguistics , philosophy
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 HIFα ubiquitination, increased accumulation of HIFα 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.