Loading…
cAMP-Mediated Stimulation of Tyrosine Hydroxylase mRNA Translation Is Mediated by Polypyrimidine-Rich Sequences within Its 3â²-Untranslated Region and Poly(C)-Binding Protein 2
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...
Saved in:
Published in: | Molecular pharmacology 2009-10, Vol.76 (4), p.872 |
---|---|
Main Authors: | , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | 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 3â²-untranslated region (UTR). In the present report, we extend these studies to show that MN9D
cytoplasmic proteins bind to the same TH mRNA 3â²-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 â¼44-kDa
protein as a major TH mRNA 3â²-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 3â²-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 3â²-UTR. This increased interaction
presumably plays a role in the activation of TH mRNA translation by cAMP in dopaminergic neurons. |
---|---|
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.109.057596 |