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Agonist Regulation of Human β2-Adrenergic Receptor mRNA Stability Occurs via a Specific AU-rich Element
Prolonged agonist stimulation of β 2 -adrenergic receptors results in receptor down-regulation, which is closely associated with a reduction of the corresponding mRNA, an effect mediated in part by changes in mRNA stability. Transfection experiments with human β 2 -adrenergic receptor cDNAs bearin...
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Published in: | The Journal of biological chemistry 1998-02, Vol.273 (6), p.3223 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Prolonged agonist stimulation of β 2 -adrenergic receptors results in receptor down-regulation, which is closely associated with a reduction of the corresponding
mRNA, an effect mediated in part by changes in mRNA stability. Transfection experiments with human β 2 -adrenergic receptor cDNAs bearing or lacking the untranslated regions suggested that the essential agonist sensitivity of
the mRNA resides within the 3â²-untranslated region. The importance of this region was further confirmed in gel shift experiments;
cytosolic preparations from agonist-stimulated DDT 1 -MF2 smooth muscle cells caused a shift of β 2 -adrenergic receptor mRNAs containing the 3â²-untranslated region. Progressive 3â²-terminal truncations of the receptor cDNA
led to the identification of an AU-rich element at positions 329â337 of the 3â²-untranslated region as the responsible cis -acting element. Substitution of this motif by cytosine residues almost completely abolished mRNA down-regulation and inhibited
the formation of the RNA-protein complex. Even though the β 2 -adrenergic receptor AU-rich element showed two U â A transitions compared with the recently proposed AU-rich element consensus
sequence, it revealed an almost identical destabilizing potency. Fusion of the β 2 -adrenergic receptor 3â²-untranslated region to the β-globin coding sequence dramatically reduced the half-life of the chimeric
transcript in an agonist- and cAMP-dependent manner. This suggests that the agonist-induced β 2 -adrenergic receptor mRNA destabilization is regulated by cAMP-dependent RNA-binding protein(s) via a specific AU-rich element. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.273.6.3223 |