Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells.

Tanaka, Keiko; Kaufman, Seymour; Milstien, Sheldon

doi:10.1073/pnas.86.15.5864

Cited by 81 publications

(39 citation statements)

References 28 publications

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“…We previously found that erythropoietic cells, despite the lack of any known BH 4 -dependent hydroxylation reactions, synthesized and contained high levels of BH 4 , which appears to play a regulatory role as a switch between growth and differentiation (52). Furthermore, we showed that proliferation of primary astrocytes was also regulated by endogenous BH 4 levels (53), results that were later confirmed in several other types of cells (54,55).…”

Section: Discussionsupporting

confidence: 62%

Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-α

Vann¹,

Twitty²,

Spiegel³

et al. 2000

Journal of Biological Chemistry

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Synthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH 4 ), a required cofactor for inducible nitric-oxide synthase (iNOS) activity, is usually coordinately regulated with iNOS expression. In C6 glioma cells, tumor necrosis factor-␣ (TNF-␣) concomitantly potentiated the stimulation of nitric oxide (NO) and BH 4 production induced by IFN-␥ and interleukin-1␤. Expression of both iNOS and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the BH 4 biosynthetic pathway, was also markedly increased, as were their activities and protein levels. Ceramide, a sphingolipid metabolite, may mediate some of the actions of TNF-␣. Indeed, we found that bacterial sphingomyelinase, which hydrolyzes sphingomyelin and increases endogenous ceramide, or the cell permeable ceramide analogue, C 2 -ceramide, but not C 2 -dihydroceramide (N-acetylsphinganine), significantly mimicked the effects of TNF-␣ on NO production and iNOS expression and activity in C6 cells. Surprisingly, although TNF-␣ increased BH 4 synthesis and GTPCH activity, neither BH 4 nor GTPCH expression was affected by C 2 -ceramide or sphingomyelinase in IFN-␥-and interleukin-1␤-stimulated cells. It is likely that increased BH 4 levels results from increased GTPCH protein and activity in vivo rather than from reduced turnover of BH 4 , because the GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, blocked cytokine-stimulated BH 4 accumulation. Moreover, expression of the GTPCH feedback regulatory protein, which if decreased might increase GTPCH activity, was not affected by TNF-␣ or ceramide. Treatment with the antioxidant pyrrolidine dithiocarbamate, which is known to inhibit NF-B and sphingomyelinase in C6 cells, or with the peptide SN-50, which blocks translocation of NF-B to the nucleus, inhibited TNF-␣-dependent iNOS mRNA expression without affecting GTPCH mRNA levels. This is the first demonstration that cytokine-stimulated iNOS and GTPCH expression, and therefore NO and BH 4 biosynthesis, may be regulated by discrete pathways. As BH 4 is also a cofactor for the aromatic amino acid hydroxylases, discovery of distinct mechanisms for regulation of BH 4 and NO has important implications for its specific functions.

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Section: Discussionsupporting

confidence: 62%

Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-α

Vann¹,

Twitty²,

Spiegel³

et al. 2000

Journal of Biological Chemistry

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“…The only pathway of apoptotic cell death that is blocked by either zVAD-fmk, olomoucine, or NAC is that of trophic factor deprivation (36,60). Previous reports suggested that BH 4 can induce cell proliferation (16,71) and that growth factor-induced proliferation correlates with endogenous BH 4 levels in PC12 cells (17). In view of these data, we postulate that BH 4 affects a growth factor-dependent signaling event, which leads to increased proliferation in the presence of sufficient trophic support or enhances cell death in its absence.…”

Section: Effect Of N-acetylcysteine or Inhibition Of Cyclin-dependentmentioning

confidence: 99%

Tetrahydrobiopterin Enhances Apoptotic PC12 Cell Death following Withdrawal of Trophic Support

Anastasiadis

Jiang

Bezin

et al. 2001

Journal of Biological Chemistry

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(6R)-Tetrahydro-L-biopterin (BH 4 ) is the rate-limiting cofactor in the production of catecholamine and indoleamine neurotransmitters and is also essential for the synthesis of nitric oxide by nitric-oxide synthase. We have previously reported that BH 4 administration induces PC12 cell proliferation and that nerve growth factor-or epidermal growth factor-induced PC12 cell proliferation requires the elevation of intracellular BH 4 levels. We show here that BH 4 accelerates apoptosis in undifferentiated PC12 cells deprived of serum and in differentiated neuron-like PC12 cells after nerve growth factor withdrawal. Increased production of catecholamines or nitric oxide cannot account for the enhancement of apoptosis by BH 4 . Furthermore, increased calcium influx by exogenous BH 4 administration is not involved in the BH 4 proapoptotic effect. Our data also argue against the possibility that increased oxidative stress, due to BH 4 autoxidation, is responsible for the observed BH 4 effects. Instead, they are consistent with the hypothesis that BH 4 induces apoptosis by increasing cell cycle progression. Elevation of intracellular BH 4 during serum withdrawal increased c-Myc (and especially Myc S) expression earlier than serum withdrawal alone. Furthermore, N-acetylcysteine and the cyclin-dependent kinase inhibitor olomoucine ameliorated the BH 4 proapoptotic effect. These data suggest that BH 4 affects c-Myc expression and cell cycle-dependent events, possibly accounting for its effects on promoting cell cycle progression or apoptosis.Apoptotic cell death is important for normal nervous system development, where neurons that make proper connections and receive sufficient trophic support survive, whereas neurons that are deprived of trophic support die via apoptosis (for a review, see Ref. 1). The requirement for neurotrophic support is thought to continue in mature neurons (for a review, see Ref.2). During normal aging and in Parkinson's disease (PD), 1 nigrostriatal dopamine neurons preferentially degenerate. The etiology of this selective cell loss remains unknown. Local availability of trophic factors is able to protect cells from degeneration in animal models of PD (3-6), suggesting that lack of trophic support could contribute to the observed neurodegeneration in normal aging and in PD. Furthermore, morphological characteristics of apoptotic cell death have been reported in brain sections from PD patients (7, 8), but the involvement of apoptosis in PD is still controversial.PC12 cells have been extensively used as a model of catecholaminergic neurons in culture as well as for the study of neuronal apoptotic death. Naive (undifferentiated) PC12 cells grown in the presence of serum undergo apoptosis upon serum withdrawal (9 -11). Furthermore, PC12 cells that become neuronally differentiated and postmitotic following prolonged incubation with NGF undergo apoptosis upon NGF and serum withdrawal (9, 10). Undifferentiated PC12 cell death upon serum withdrawal has been linked to an inappropriate progression through th...

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“…Why extracellular, but not intracellular, BH4 is toxic is not clear at present. Interestingly, elevation of intracellular BH4 has been reported to enhance proliferation (Tanaka et al, 1989;Anastasiadis et al, 1996) and to protect cells against oxidative stressors (Ishii et al, 1999;Nakamura et al, 2000) in various cell types. We have also observed in the present study that elevation of intracellular BH4 with sepiapterin was not toxic.…”

Section: Downloaded Frommentioning

confidence: 99%

Tetrahydrobiopterin Is Released from and Causes Preferential Death of Catecholaminergic Cells by Oxidative Stress

et al. 2000

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The underlying cause of the selective death of the nigral dopaminergic neurons in Parkinson's disease is not fully understood. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of dopamine and nitric oxide. Because BH4 contributes to the syntheses of these two potential oxidative stressors and also undergoes autoxidation, thereby producing reactive oxygen species, it was possible that BH4 may play a role in the selective vulnerability of dopaminergic cells. BH4 given extracellularly was cytotoxic to catecholamine cells CATH.a, SK-N-BE(2)C, and PC12, but not to noncatecholamine cells RBL-2H3, CCL-64, UMR-106-01, or TGW-nu-1. This was not caused by increased dopamine or nitric oxide, because inhibition of their syntheses did not attenuate the damage and BH4 did not raise their cellular levels. Dihydrobiopterin and biopterin were not toxic, indicating that the fully reduced form is responsible. The toxicity was caused by generation of reactive oxygen species, because catalase, superoxide dismutase, and peroxidase protected the cells from the BH4-induced demise. Furthermore, thiol agents, such as reduced glutathione, dithiothreitol, ␤-mercaptoethanol, and N-acetylcysteine were highly protective. The BH4 toxicity was initiated extracellularly, because elevation of intracellular BH4 by sepiapterin did not result in cell damage. BH4 was spontaneously released from the cells of its synthesis to a large extent, and the release was not further enhanced by calcium influx. This BH4-induced cytotoxicity may represent a mechanism by which selective degeneration of dopaminergic terminals and neurons occur.

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Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells.

Cited by 81 publications

References 28 publications

Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-α

Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-α

Tetrahydrobiopterin Enhances Apoptotic PC12 Cell Death following Withdrawal of Trophic Support

Tetrahydrobiopterin Is Released from and Causes Preferential Death of Catecholaminergic Cells by Oxidative Stress

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