Tetrahydrobiopterin Enhances Apoptotic PC12 Cell Death following Withdrawal of Trophic Support

Panos Z. Anastasiadis, Hao Jiang, Laurent Bezin, Donald M. Kuhn, Robert A. Levine

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

(6R)-Tetrahydro-L-biopterin (BH4) 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 BH4 administration induces PC12 cell proliferation and that nerve growth factor- or epidermal growth factor-induced PC12 cell proliferation requires the elevation of intracellular BH4 levels. We show here that BH4 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 BH4. Furthermore, increased calcium influx by exogenous BH 4 administration is not involved in the BH4 proapoptotic effect. Our data also argue against the possibility that increased oxidative stress, due to BH4 autoxidation, is responsible for the observed BH4 effects. Instead, they are consistent with the hypothesis that BH4 induces apoptosis by increasing cell cycle progression. Elevation of intracellular BH4 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 BH4 proapoptotic effect. These data suggest that BH4 affects c-Myc expression and cell cycle-dependent events, possibly accounting for its effects on promoting cell cycle progression or apoptosis.

Original languageEnglish (US)
Pages (from-to)9050-9058
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number12
DOIs
StatePublished - Mar 23 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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