Inhibition of calmodulin-dependent phosphodiesterase induces apoptosis in human leukemic cells.

Article Details


Jiang X, Li J, Paskind M, Epstein PM

Inhibition of calmodulin-dependent phosphodiesterase induces apoptosis in human leukemic cells.

Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11236-41.

PubMed ID
8855339 [ View in PubMed

Cytosolic extracts from a human lymphoblastoid B-cell line, RPMI-8392, established from a patient with acute lymphocytic leukemia, contain two major forms of cyclic nucleotide phosphodiesterase (PDE): Ca2+-calmodulin dependent PDE (PDE1) and cAMP-specific PDE (PDE4). In contrast, normal quiescent human peripheral blood lymphocytes (HPBL) are devoid of PDE1 activity [Epstein, P. M., Moraski, S., Jr., and Hachisu, R. (1987) Biochem. J. 243, 533-539]. Using reverse transcription-polymerase chain reaction (RT-PCR), we show that the mRNA encoding the 63-kDa form of PDE1 (PDE1B1) is expressed in RPMI-8392 cells, but not in normal, resting HPBL. This mRNA is, however, induced in HPBL following mitogenic stimulation by phytohemagglutinin (PHA). Also using RT-PCR, the full open reading frame for human PDE1B1 cDNA was cloned from RPMI-8392 cells and it encodes a protein of 536 amino acids with 96% identity to bovine, rat, and mouse species. RT-PCR also identifies the presence of PDE1B1 in other human lymphoblastoid and leukemic cell lines of B- (RPMI-1788, Daudi) and T-(MOLT-4, NA, Jurkat) cell origin. Inhibition of PDE1 or PDE4 activity by selective inhibitors induced RPMI-8392 cells, as well as the other cell lines, to undergo apoptosis. Culture of RPMI-8392 cells with an 18-bp phosphorothioate antisense oligodeoxynucleotide, targeted against the translation initiation region of the RPMI-8392 mRNA, led to a specific reduction in the amount of PDE1B1 mRNA after 1 day, and its disappearance after 2 days, and induced apoptosis in these cells in a sequence specific manner. This suggests that PDEs, particularly PDE1B1, because its expression is selective, may be useful targets for inducing the death of leukemic cells.

DrugBank Data that Cites this Article

NameUniProt ID
Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1BQ01064Details