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Inhibition of Cyclin D1 Expression and Phosphorylation of Retinoblastoma Protein by Phosmidosine, a Nucleotide Antibiotic¹

Antibiotics Laboratory, The Institute of Physical and Chemical Research (RIKEN), Saitama 351-0198, Japan [H. K., R. O., C. O., H. O.], and Department of Environmental Toxicology, and Institute of Toxicology and Environmental Health, University of California, Davis, California 95695 [P. C.-C. L., F. M.]

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.

¹ This work was supported in part by a Special Grant for Promotion of Research (RIKEN), a Grant for Multibioprobes (RIKEN), and a Grant from the Ministry of Education, Science, Sports and Culture, Japan.

² Present address: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0606.

³ To whom requests for reprints should be addressed, at The Institute of Physical and Chemical Research, RIKEN, Hirosawa 2-1, Wako-shi, Saitama 351-01, Japan. Phone: 81-48-467-9541; Fax: 81-48-462-4669; E-mail: antibiot@postman.riken.go.jp.

Received 9/ 3/97. Accepted 12/16/97.

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