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Papers In Press, published online ahead of print July 16, 2002
Division of Therapeutics, Nottingham University, University Hospital, Nottingham NG7 2UH
Corresponding Author: ivan.lejeune{at}nottingham.ac.uk
Phosphodiesterase 4D (PDE4D), part of the complex cAMP-specific PDE4 family, plays a pivotal role in the regulation of airway smooth muscle relaxation by catalysing the hydolysis of cAMP. Its gene on chromosome 5q12 encodes 5 splice-variants, which show tissue-dependent expression and regulation. The genomic arrangement of PDE4D was determined using in silico methods and a putative promoter of one of the protein kinase A (PKA) activated, long isoforms, PDE4D5 was identified. Promoter-luciferase constructs, transiently-transfected into a ß2 adrenoceptor-expressing CHO-K1 cell line, were used to demonstrate that the PDE4D5 promoter upregulated reporter gene expression in response to increased cell cAMP. Site-directed mutagenesis of the cAMP-response element (CRE) at position -201 identified this as the principle component of the mechanism underlying this cAMP-responsiveness. In the second part of this study, cAMP-dependent induction of PDE4D5 transcript in primary-cultured human airway smooth muscle cells (hASMs) was demonstrated using both qualitative reverse-transcriptase PCR and quantitative real-time PCR. Isolated PDE4D5 isoenzyme activity, measured after selective immuno-precipitation from hASMs, confirmed that this increase in expression led to an upregulation of functional activity. We present evidence for cAMP-driven PDE4D5 upregulation in hASMs and suggest a CRE-containing, isoform-specific promoter as the primary mechanism.
J. Biol. Chem, 10.1074/jbc.M204832200
Submitted on May 16, 2002
Revised on July 15, 2002
Accepted on July 16, 2002
Cyclic AMP-dependent transcriptional upregulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterisation of a novel PDE4D5 promoter
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