INHIBITION OF CYCLIN D1 EXPRESSION AND PHOSPHORYLATION OF RETINOBLASTOMA PROTEIN BY PHOSMIDOSINE, A NUCLEOTIDE ANTIBIOTIC

In this report, we studied the effect of phosmidosine, a proline-conta ining nucleotide on the serum-induced cell cycle progression in human lung fibroblast WI-38 cells. Phosmidosine suppressed S-phase entry and arrested cell cycle progression at the G(1) phase. In serum-stimulate d cells, phosmidosine did not affect the activation of the mitogen-act ivated protein kinase cascade. However, phosmidosine inhibited hyperph osphorylation of retinoblastoma (RB) protein by RB-kinases such as cyc lin-dependent kinase 4 and cyclin-dependent kinase 2, probably as a re sult of the inhibition of cyclin D1 expression. Furthermore, in tsFT21 0 cells, a temperature-sensitive cdc2 mutant isolated from the mouse m ammary carcinoma cell line FM3A, phosmidosine, irreversibly inhibited the cell cycle progression at G(1) without affecting the G(2) to M tra nsition. Phosmidosine acts at an earlier point in G(1) compared with m imosine or aphidicolin, well-known cell cycle blockers at the G(1)-S b oundary. Taken together, phosmidosine arrested cells at a specific poi nt between the start point and restriction point in G, and is a useful drug that may contribute to the understanding of the regulatory mecha nisms of G(1) progression.