PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP.
PDE7A is a recently described 3',5'-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) whose expression has been detected in T-cells. As treatment with the methylxanthine theophylline, a nonspecific PDE inhibitor, induces apoptosis in leukemic cells from patients with the B-lineage malignancy chronic lymphocytic leukemia (CLL), we sought to determine if PDE7A was a target of theophylline therapy in such cells. Western analysis revealed expression of PDE7A in normal human splenic B-cells, primary CLL cells, and in a CLL-derived cell line (WSU-CLL). Among the six cAMP PDEs (PDE1B, PDE3B, PDE4A, PDE4B, PDE4D, and PDE7) examined in WSU-CLL, only PDE7A levels were augmented by treatment with methylxanthines. The activity of PDE7A isolated from the WSU-CLL cell line by immunoprecipitation was inhibited by theophylline and IBMX with IC50 values of 343.5 and 8.6 microM, respectively. WSU-CLL PDE7A was also up-regulated by a novel specific inhibitor (IC242), which inhibits PDE7A from WSU-CLL cells with an IC50 value of 0.84 microM. IC242-mediated up-regulation of PDE7A was blocked by the protein kinase A (PKA) inhibitor H-89.
Lee
Richard
R
Section of Hematology and Oncology, Department of Medicine, EBRC 420, Boston Medical Center, 650 Albany Street, Boston, MA 02118, USA.
Wolda
Sharon
S
Moon
Eunyi
E
Esselstyn
James
J
Hertel
Carmen
C
Lerner
Adam
A
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007424:Intracellular Fluid; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D015459:Leukemia-Lymphoma, Adult T-Cell; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D013154:Spleen / Q000166:cytology; D013806:Theophylline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014970:Xanthines / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D005576:Colforsin; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517291:PDE3B protein, human; C517355:PDE4A protein, human; C517360:PDE4B protein, human; C517376:PDE4D protein, human; D015056:1-Methyl-3-isobutylxanthine