Inhibition of cyclin D1 expression and phosphorylation of retinoblastoma protein by phosmidosine, a nucleotide antibiotic.

Abstract

In this report, we studied the effect of phosmidosine, a proline-containing 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 G1 phase. In serum-stimulated cells, phosmidosine did not affect the activation of the mitogen-activated protein kinase cascade. However, phosmidosine inhibited hyperphosphorylation of retinoblastoma (RB) protein by RB-kinases such as cyclin-dependent kinase 4 and cyclin-dependent kinase 2, probably as a result of the inhibition of cyclin D1 expression. Furthermore, in tsFT210 cells, a temperature-sensitive cdc2 mutant isolated from the mouse mammary carcinoma cell line FM3A, phosmidosine, irreversibly inhibited the cell cycle progression at G1 without affecting the G2 to M transition. Phosmidosine acts at an earlier point in G1 compared with mimosine or aphidicolin, well-known cell cycle blockers at the G1-S boundary. Taken together, phosmidosine arrested cells at a specific point between the start point and restriction point in G1 and is a useful drug that may contribute to the understanding of the regulatory mechanisms of G1 progression.

• Authors: H Kakeya, R Onose, P C Liu, C Onozawa, F Matsumura, H Osada
• Journal: Cancer research (Cancer Res) Vol. 58 Issue 4 Pg. 704-10 (Feb 15 1998) ISSN: 0008-5472 [Print] United States
• PMID: 9485024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Purine Nucleotides
• Retinoblastoma Protein
• phosmidosine
• Cyclin D1
• Calcium-Calmodulin-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Cell Cycle (drug effects)
• Cyclin D1 (metabolism)
• Enzyme Activation
• Humans
• Mice
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Phosphorylation
• Purine Nucleotides (pharmacology)
• Retinoblastoma Protein (metabolism)
• Tumor Cells, Cultured