Regulation of Tyrosine Hydroxylase Gene Expression in the Rat Carotid Body by Hypoxia

Czyzyk-Krzeska, Maria F.; Bayliss, Douglas A.; Lawson, Edward E.; Millhorn, David E.

doi:10.1111/j.1471-4159.1992.tb11376.x

Cited by 182 publications

(125 citation statements)

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“…However, administration of an endothelin receptor antagonist did not block ventilatory responses to hypoxia (27). Expression of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine biosynthesis, is also induced by hypoxia in the carotid body (28).…”

Section: Discussionmentioning

confidence: 99%

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

238

216

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To investigate whether the transcriptional activator hypoxiainducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O 2-regulated HIF-1␣ subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a ϩ/Ϫ mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a ϩ/Ϫ mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a ϩ/Ϫ mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a ϩ/Ϫ mice. Thus partial HIF-1␣ deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.O xygen homeostasis is mediated by the combined physiologic functioning of the circulatory and respiratory systems. Recent studies have demonstrated that the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for both the establishment of the circulatory system during embryonic development and physiologic responses in postnatal life. Analysis of Hif1a Ϫ/Ϫ knockout mice, which are homozygous for a lossof-function mutation in the Hif1a gene encoding the O 2 -regulated HIF-1␣ subunit, revealed that complete HIF-1␣ deficiency results in embryonic lethality at midgestation with major malformations of the heart and vasculature (1-3). Hif1a ϩ/Ϫ heterozygous mice, which are partially HIF-1␣ deficient, develop normally and are indistinguishable from their wild-type littermates under normoxic conditions. However, adult Hif1a ϩ/Ϫ mice manifest impaired physiological responses to chronic hypoxia including significantly reduced rates of erythropoiesis and pulmonary vascular remodeling (4). Thus HIF-1␣ plays essential roles in cardiac, erythroid, and vascular development and physiology, i.e., all three major components of the circulatory system.An essential adaptation to both acute and chronic hypoxia is an increase in ventilation that depends on the activity of peripheral chemoreceptors, particularly those within the carotid body, which detect changes in arterial blood O 2 concentration and relay sensory information to the brainstem neurons that regulate breathing (reviewed in ref. 5). Altered ventilatory responses to hypoxia may play a critical role in asthma, diabetes, Parkinson's disease, sleep-related breathing disorders, and sudden infant death syndrome (6-8). We hypothesized that HIF-1␣ is required for carotid body function and ventilatory adaptation to chronic hypoxia. To test this hyp...

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Section: Discussionmentioning

confidence: 99%

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

238

216

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“…Therefore, we next asked whether the Ser 133 phosphorylation of CREB resulted in functional activation of a hypoxiaregulated gene. Expression of the TH gene has been shown to be activated in response to physiological levels of hypoxia both in vivo (42) and in vitro (10). The rat TH gene contains a consensus CRE localized at Ϫ45 to Ϫ38 nucleotides relative to the transcriptional start site (43).…”

Section: Resultsmentioning

confidence: 99%

“…It has been established previously that TH gene expression is induced by hypoxia both in vivo (42) and in PC12 cells (10). The TH gene contains a CRE that has been shown to be critical for cAMP-and Ca 2ϩ -induced activation of gene expression (25,44,53,54).…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia Induces Phosphorylation of the Cyclic AMP Response Element-binding Protein by a Novel Signaling Mechanism

Beitner‐Johnson

Millhorn

1998

Journal of Biological Chemistry

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125

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To investigate signaling mechanisms by which hypoxia regulates gene expression, we examined the effect of hypoxia on the cyclic AMP response element-binding protein (CREB) in PC12 cells. Exposure to physiological levels of hypoxia (5% O 2 , ϳ50 mm Hg) rapidly induced a persistent phosphorylation of CREB on Ser 133 , an event that is required for CREB-mediated transcriptional activation. Hypoxia-induced phosphorylation of CREB was more robust than that induced by any other stimulus tested, including forskolin, depolarization, and osmotic stress. Furthermore, this effect was not mediated by any of the previously known signaling pathways that lead to phosphorylation of CREB, including protein kinase A, calcium/calmodulin-dependent protein kinase, protein kinase C, ribosomal S6 kinase-2, and mitogenactivated protein kinase-activated protein kinase-2. Hypoxic activation of a CRE-containing reporter (derived from the 5-flanking region of the tyrosine hydroxylase gene) was attenuated markedly by mutation of the CRE. Thus, a physiological reduction in O 2 levels induces a functional phosphorylation of CREB at Ser 133 via a novel signaling pathway.

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“…Cells respond to hypoxia by regulating the expression of a number of genes, including erythropoietin, vascular endothelial growth factor, and various glycolytic enzymes (2)(3)(4)(5). This regulation is mediated in part by transcription factors of the hypoxia-inducible factor (HIF) 1 family (6).…”

mentioning

confidence: 99%

Cobalt Inhibits the Interaction between Hypoxia-inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia-inducible Factor-α

Yuan

Hilliard

Ferguson

et al. 2003

Journal of Biological Chemistry

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573

411

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The hypoxia-inducible factor (HIF) activates the expression of genes that contain a hypoxia response element. The ␣-subunits of the HIF transcription factors are degraded by proteasomal pathways during normoxia but are stabilized under hypoxic conditions. The von Hippel-Lindau protein (pVHL) mediates the ubiquitination and rapid degradation of HIF-␣ (including HIF-1␣ and HIF-2␣). Post-translational hydroxylation of a proline residue in the oxygen-dependent degradation (ODD) domain of HIF-␣ is required for the interaction between HIF and VHL. It has previously been established that cobalt mimics hypoxia and causes accumulation of HIF-1␣ and HIF-2␣. However, little is known about the mechanism by which this occurs. In an earlier study, we demonstrated that cobalt binds directly to the ODD domain of HIF-2␣. Here we provide the first evidence that cobalt inhibits pVHL binding to HIF-␣ even when HIF-␣ is hydroxylated. Deletion of 17 amino acids within the ODD domain of HIF-2␣ that are required for pVHL binding prevented the binding of cobalt and stabilized HIF-2␣ during normoxia. These findings show that cobalt mimics hypoxia, at least in part, by occupying the VHL-binding domain of HIF-␣ and thereby preventing the degradation of HIF-␣.Hypoxia is a critical stimulus in many physiological and disease states (1). Cells respond to hypoxia by regulating the expression of a number of genes, including erythropoietin, vascular endothelial growth factor, and various glycolytic enzymes (2-5). This regulation is mediated in part by transcription factors of the hypoxia-inducible factor (HIF) 1 family (6). HIF-1␣ and HIF-2␣ are basic helix-loop-helix Per-Arnt-Sim (PAS) domain proteins (7) that form a heterodimer with the aryl hydrocarbon nuclear receptor translocator protein. Previous studies have shown that HIF-1␣ protein accumulates rapidly during hypoxia without a significant increase in HIF-1␣ mRNA levels (8). HIF-2␣, which is also known as endothelial PAS domain protein-1, shares close sequence and structural homology with HIF-1␣ (9). Like HIF-1␣, the levels of HIF-2␣ protein are low during normoxia and accumulate when cells are exposed to hypoxia, proteasomal inhibitors, transition metals (e.g. cobalt), iron chelators, or reducing agents (10). During normoxia, the HIF-␣ (HIF-1␣ and HIF-2␣ are referred to here simply as HIF-␣, except where noted otherwise) proteins are continuously degraded by ubiquitin-and proteasome-dependent pathway. Detailed studies of HIF-␣ proteins revealed a 200-amino acid sequence, called the oxygen-dependent degradation domain (ODD) that is responsible for its degradation in the presence of oxygen (11,12). The von Hippel-Lindau (pVHL) protein, a tumor suppressor protein, mediates the ubiquitination and degradation of HIF-␣ by binding to the ODD domain under conditions of normoxia (13,14). Recent findings revealed that pVHL-mediated degradation requires hydroxylation of specific proline residues within the ODD (15-18). The hydroxylation of these proline residues may be critical for regulating the HI...

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Regulation of Tyrosine Hydroxylase Gene Expression in the Rat Carotid Body by Hypoxia

Cited by 182 publications

References 34 publications

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Hypoxia Induces Phosphorylation of the Cyclic AMP Response Element-binding Protein by a Novel Signaling Mechanism

Cobalt Inhibits the Interaction between Hypoxia-inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia-inducible Factor-α

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