Cytokine suppression of dopamine-β-hydroxylase by extracellular signal-regulated kinase-dependent and -independent pathways

Suzan Dziennis, Beth Habecker

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Cholinergic differentiation factors (CDFs) suppress noradrenergic properties and induce cholinergic properties in sympathetic neurons. The CDFs leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) bind to a LIFR·gp130 receptor complex to activate Jak/signal transducers and activators of transcription and Ras/mitogen-activated protein kinases signaling pathways. Little is known about how these differentiation factors suppress noradrenergic properties. We used sympathetic neurons and SK-N-BE(2)M17 neuroblastoma cells to investigate CDF down-regulation of the norepinephrine synthetic enzyme dopamine-β-hydroxylase (DBH). LIF and CNTF activated extracellular signal-regulated kinases (ERKs) 1 and 2 but not p38 or Jun N-terminal kinases in both cell types. Preventing ERK activation with PD98059 blocked CNTF suppression of DBH protein in sympathetic neurons but did not prevent the loss of DBH mRNA. CNTF decreased transcription of a DBH promoter-luciferase reporter construct in SK-N-BE(2)M17 cells, and this was also ERK-independent. Cytokine inhibition of DBH promoter activity did not require a silencer element but was prevented by overexpression of the transcriptional activator Phox2a. Inhibiting ERK activation increased basal DBH transcription in SK-N-BE(2)M17 cells, and DBH mRNA in sympathetic neurons. Transfection of Phox2a into PD98059-treated M17 cells resulted in a synergistic increase in DBH promoter activity compared with Phox2a or PD98059 alone. These data suggest that CDFs down-regulate DBH protein via an ERK-dependent pathway but inhibit DBH gene expression through an ERK-independent pathway. They further suggest that ERK activity inhibits basal DBH gene expression.

Original languageEnglish (US)
Pages (from-to)15897-15904
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
StatePublished - May 2 2003

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Leukemia Inhibitory Factor
Extracellular Signal-Regulated MAP Kinases
Mixed Function Oxygenases
Ciliary Neurotrophic Factor
Dopamine
Cytokines
Neurons
Transcription
Gene expression
Down-Regulation
Chemical activation
Transcriptional Silencer Elements
Gene Expression
Messenger RNA
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Luciferases
Transducers
Neuroblastoma

ASJC Scopus subject areas

  • Biochemistry

Cite this

Cytokine suppression of dopamine-β-hydroxylase by extracellular signal-regulated kinase-dependent and -independent pathways. / Dziennis, Suzan; Habecker, Beth.

In: Journal of Biological Chemistry, Vol. 278, No. 18, 02.05.2003, p. 15897-15904.

Research output: Contribution to journalArticle

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