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Potent and Specific Inhibition of p60^v-src Protein Kinase Both in Vivo and in Vitro by Radicicol¹

Department of Agricultural Chemistry, Faculty of Agriculture, Tokyo University, Bunkyo-ku, Tokyo 113, Japan

² To whom requests for reprints should be addressed, at Department of Agricultural Chemistry, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113, Japan.

A fungal metabolite, radicicol, with a macrocyclic ring induced the reversal of transformed phenotypes of v-src-transformed fibroblasts (Rous sarcoma virus-transformed 3Y1 rat fibroblast) at a quite low concentration of 0.1 µg/ml. Actin stress fibers reappeared in the transformed cells after treatment with radicicol. Radicicol reduced the intra-cellular level of autophosphorylation of p60^v-src as well as the level of other tyrosine-phosphorylated proteins in a dose-dependent manner. In vitro kinase assay revealed that radicicol effectively inhibited not only autophosphorylation but also transphosphorylation activities of purified p60^v-src with a concentration producing 50% inhibition of 0.1 µg/ml. However, radicicol showed no inhibitory effect on protein kinase C or protein kinase A. These results suggest that radicicol is a novel and specific protein-tyrosine kinase inhibitor and that the decreased level of tyrosine kinase activity of p60^v-src causes reversion of transformed phenotypes of Rous sarcoma virus-transformed 3Y1 rat fibroblast. Furthermore, differentiation of Friend leukemia cells, which is one of the known characteristic phenomena associated with the inhibition of tyrosine kinase, was also induced in the concentration range of 0.05–0.5 µg/ml, suggesting that the agent is useful for the analysis of differentiation as well as the kinase-mediated signal transduction.

¹ This work was supported by a grant-in-aid for Cancer Research from the Ministry of Education, Science, and Culture, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/15/92. Accepted 9/28/92.

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