title: Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is a pharmacological target of differentiation-inducing factor-1, an antitumor agent isolated from Dictyostelium.
abstract: The differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum is a potent antiproliferative agent that induces growth arrest and differentiation in mammalian cells in vitro. However, the specific target molecule(s) of DIF-1 has not been identified. In this study, we have tried to identify the target molecule(s) of DIF-1 in mammalian cells, examining the effects of DIF-1 and its analogs on the activity of some candidate enzymes. DIF-1 at 10-40 micro M dose-dependently suppressed cell growth and increased the intracellular cyclic AMP concentration in K562 leukemia cells. It was then found that DIF-1 at 0.5-20 micro M inhibited the calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase (PDE1) in vitro in a dose-dependent manner. Kinetic analysis revealed that DIF-1 acted as a competitive inhibitor of PDE1 versus the substrate cyclic AMP. Because DIF-1 did not significantly affect the activity of other PDEs or CaM-dependent enzymes and, in addition, an isomer of DIF-1 was a less potent inhibitor, we have concluded that PDE1 is a pharmacological and specific target of DIF-1.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Mie University, Mie, Japan.
authors.forename: Kasumi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Taku
authors.initials: T
authors.lastname: Murata
authors.forename: Toshiro
authors.initials: T
authors.lastname: Tagawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takahashi
authors.forename: Ryoki
authors.initials: R
authors.lastname: Ishikawa
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Abe
authors.forename: Kohei
authors.initials: K
authors.lastname: Hosaka
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kubohara
mesh_terms: D001667:Binding, Competitive; D000242:Cyclic AMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D006588:Hexanones / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*
chemical_list: D006588:Hexanones; D010726:Phosphodiesterase Inhibitors; C053433:1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1