[Screening of phosphatidylinositol turnover inhibitors and regulation of cell cycle progression].
Phosphatidylinositol (PI) turnover is considered to be involved in the regulation of cell growth. The enzymes for PI turnover include phospholipase C (PLC), PI4-kinase and PI synthase. We have isolated pholipeptin and fluvirucin B2 from microorganisms and akaterpin from a marine sponge as PLC gamma inhibitors. We also isolated echiguanines from Streptomyces as PI4-kinase inhibitors. Since echiguanines did not inhibit the enzyme in situ, we synthesized their ribosylated derivatives that were effective in cultured cells. We previously isolated inostamycin from Streptomyces as an inhibitor of PI synthase. We found that inostamycin induced G1 block in cycling NRK cells. Inostamycin inhibited the serum-induced S-phase induction in quiescent NRK cells. Inostamycin was found to decrease serum-induced expression of cyclin D and cyclin E, without inhibiting the activation of MAP kinase. It also inhibited serum-induced activation of CDK2 and phosphorylation of pRB. Thus, PI synthesis was suggested to be involved in regulation of serum-induced S-phase induction by modulating G1 cyclin expression.
Umezawa
K
K
Faculty of Science and Technology, Keio University.
Deguchi
A
A
Imoto
M
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; D005663:Furans; D010716:Phosphatidylinositols; C071861:inostamycin; D010738:Type C Phospholipases