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Molecular Pharmacology

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cAMP-Mediated Stimulation of Tyrosine Hydroxylase mRNA Translation Is Mediated by Polypyrimidine-Rich Sequences within Its 3′-Untranslated Region and Poly(C)-Binding Protein 2

Lu Xu, Carol R. Sterling and A. William Tank
Molecular Pharmacology October 2009, 76 (4) 872-883; DOI: https://doi.org/10.1124/mol.109.057596
Lu Xu
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Abstract

Tyrosine hydroxylase (TH) plays a critical role in maintaining the appropriate concentrations of catecholamine neurotransmitters in brain and periphery, particularly during long-term stress, long-term drug treatment, or neurodegenerative diseases. Its expression is controlled by both transcriptional and post-transcriptional mechanisms. In a previous report, we showed that treatment of rat midbrain slice explant cultures or mouse MN9D cells with cAMP analog or forskolin leads to induction of TH protein without concomitant induction of TH mRNA. We further showed that cAMP activates mechanisms that regulate TH mRNA translation via cis-acting sequences within its 3′-untranslated region (UTR). In the present report, we extend these studies to show that MN9D cytoplasmic proteins bind to the same TH mRNA 3′-UTR domain that is required for the cAMP response. RNase T1 mapping demonstrates binding of proteins to a 27-nucleotide polypyrimidine-rich sequence within this domain. A specific mutation within the polypyrimidine-rich sequence inhibits protein binding and cAMP-mediated translational activation. UV-cross-linking studies identify a ∼44-kDa protein as a major TH mRNA 3′-UTR binding factor, and cAMP induces the 40- to 42-kDa poly(C)-binding protein-2 (PCBP2) in MN9D cells. We show that PCBP2 binds to the TH mRNA 3′-UTR domain that participates in the cAMP response. Overexpression of PCBP2 induces TH protein without concomitant induction of TH mRNA. These results support a model in which cAMP induces PCBP2, leading to increased interaction with its cognate polypyrimidine binding site in the TH mRNA 3′-UTR. This increased interaction presumably plays a role in the activation of TH mRNA translation by cAMP in dopaminergic neurons.

  • TH, tyrosine hydroxylase
  • PCBP, poly(C)-binding protein
  • 8-CPT-cAMP, 8-chlorophenylthio-cAMP
  • PBS, phosphate-buffered saline
  • UTR, untranslated region
  • PCR, polymerase chain reaction
  • RT-PCR, reverse transcription-polymerase chain reaction
  • DEPC, diethyl pyrocarbonate
  • nt, nucleotide
  • Ad, adenosine
  • KA, KpnI and ApaI sites
  • AS, ApaI and SphI
  • bp, base pair.

Footnotes

  • The work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA05014] and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS39415].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • ABBREVIATIONS:

    • Received May 7, 2009.
    • Accepted July 20, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (4)
Molecular Pharmacology
Vol. 76, Issue 4
October 2009
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cAMP-Mediated Stimulation of Tyrosine Hydroxylase mRNA Translation Is Mediated by Polypyrimidine-Rich Sequences within Its 3′-Untranslated Region and Poly(C)-Binding Protein 2

Lu Xu, Carol R. Sterling and A. William Tank
Molecular Pharmacology October 1, 2009, 76 (4) 872-883; DOI: https://doi.org/10.1124/mol.109.057596

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cAMP-Mediated Stimulation of Tyrosine Hydroxylase mRNA Translation Is Mediated by Polypyrimidine-Rich Sequences within Its 3′-Untranslated Region and Poly(C)-Binding Protein 2

Lu Xu, Carol R. Sterling and A. William Tank
Molecular Pharmacology October 1, 2009, 76 (4) 872-883; DOI: https://doi.org/10.1124/mol.109.057596
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