Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclicAMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways - A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells

Multiple families of cyclic nucleotide phosphodiesterases (PDE) have been d escribed, and the regulated expression of these genes in cells is complex. Although cAMP is known to control the expression of certain PDE in cells, p resumably reflecting a system of feedback on cAMP signaling, relatively lit tle is known about the influence of non-cAMP signaling systems on PDE expre ssion. In this study, we describe a novel mechanism by which activators of the protein kinase C (PKC)-Raf-MEK-ERK cascade regulate phosphodiesterase 4 D (PDE4D) expression in vascular smooth muscle cells (VSMC) and assess the functional consequences of this effect. Whereas a prolonged elevation of cA MP in VSMC resulted in a protein kinase A (PHA)-dependent induction of expr ession of two PDE4D variants (PDE4D1 and PDE4D2), simultaneous activation o f both the cAMP/-PKA and PRC-Raf-MER-ERK signaling cascades blunted this cA MP-mediated increase in PDE4D expression. By using biochemical, molecular b iological, and pharmacological approaches, we demonstrate that this PDE4D-s elective effect of activators of the PKC-Raf-MEK-ERK cascade was mediated t hrough a mechanism involving altered PDE4D mRNA stability and markedly atte nuated the cAMP-mediated desensitization that results from prolonged activa tion of the cAMP signaling system in cells. The data are presented in the c ontext of activators of the PKC-Raf-MEK-ERK cascade having both short and l ong term effects on PDE4D activity and expression in cells that may influen ce cAMP signaling.