Mitogenic effects of tetrahydrobiopterin in PC12 cells

Panagiotis Z Anastasiadis, J. Christopher States, Bruce A. Imerman, Marisa C. Louie, Donald M. Kuhn, Robert A. Levine

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

(6R)-5,6,7,8-Tetrahydrobiopterin (BH4), which is synthesized intracellularly from GTP, caused a concentration-dependent increase in rat pheochromocytoma (PC12) cell proliferation when added exogenously. Incubation with sepiapterin, which is converted enzymatically to BH4 within cells, also increased PC12 cell proliferation and BH4 levels concomitantly. These sepiapterin effects were mediated by BH4 as inhibition of sepiapterin conversion to BH4 by a sepiapterin reductase inhibitor, N-acetyl-serotonin, blocked the increase in proliferation and the elevation of BH4 levels. 7,8- Dihydrobiopterin (BH2) also increased BH4 levels and PC12 cell proliferation, both of which were reversed by methotrexate, which blocks the conversion of BH2 to BH4 by dihydrofolate reductase. The BH4-induced increase in PC12 cell proliferation was not related to elevated catecholamine or nitric oxide synthesis as inhibitors of tyrosine hydroxylase or nitric oxide synthase did not reduce the BH4 effect. BH4 and its precursors did not alter intracellular cAMP levels, suggesting that this second messenger is not involved in the enhancement of PC12 cell proliferation by BH4. Sepiapterin and BH4 also enhanced the proliferation of SV40-transformed human fibroblasts and rat C6 glioma cells, indicating that the stimulatory effect of BH4 on cell proliferation is not restricted to PC12 cells.

Original languageEnglish (US)
Pages (from-to)149-155
Number of pages7
JournalMolecular Pharmacology
Volume49
Issue number1
StatePublished - Jan 1996
Externally publishedYes

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PC12 Cells
Cell Proliferation
sepiapterin reductase
Tetrahydrofolate Dehydrogenase
Tyrosine 3-Monooxygenase
Second Messenger Systems
Pheochromocytoma
Guanosine Triphosphate
Methotrexate
Nitric Oxide Synthase
Glioma
Catecholamines
sapropterin
Serotonin
Nitric Oxide
Fibroblasts
sepiapterin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anastasiadis, P. Z., States, J. C., Imerman, B. A., Louie, M. C., Kuhn, D. M., & Levine, R. A. (1996). Mitogenic effects of tetrahydrobiopterin in PC12 cells. Molecular Pharmacology, 49(1), 149-155.

Mitogenic effects of tetrahydrobiopterin in PC12 cells. / Anastasiadis, Panagiotis Z; States, J. Christopher; Imerman, Bruce A.; Louie, Marisa C.; Kuhn, Donald M.; Levine, Robert A.

In: Molecular Pharmacology, Vol. 49, No. 1, 01.1996, p. 149-155.

Research output: Contribution to journalArticle

Anastasiadis, PZ, States, JC, Imerman, BA, Louie, MC, Kuhn, DM & Levine, RA 1996, 'Mitogenic effects of tetrahydrobiopterin in PC12 cells', Molecular Pharmacology, vol. 49, no. 1, pp. 149-155.
Anastasiadis PZ, States JC, Imerman BA, Louie MC, Kuhn DM, Levine RA. Mitogenic effects of tetrahydrobiopterin in PC12 cells. Molecular Pharmacology. 1996 Jan;49(1):149-155.
Anastasiadis, Panagiotis Z ; States, J. Christopher ; Imerman, Bruce A. ; Louie, Marisa C. ; Kuhn, Donald M. ; Levine, Robert A. / Mitogenic effects of tetrahydrobiopterin in PC12 cells. In: Molecular Pharmacology. 1996 ; Vol. 49, No. 1. pp. 149-155.
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