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Mechanism of Reversion of Rous Sarcoma Virus Transformation by Herbimycin A: Reduction of Total Phosphotyrosine Levels Due to Reduced Kinase Activity and Increased Turnover of p60^v-src1

Department of Antibiotics, The National Institute of Health, 2-10-35 Kamiosaki, Shinagawa-ku, Tokyo 141, Japan [Y. U., Y. M., S. M.]; and Aging Process Research Laboratory (Frontier Research Program), Tsukuba Life Science Center, RIKEN, Koyadai, Tsukuba-shi Ibaraki 305, Japan [Y. S.]

We studied the mechanism of reversion of Rous sarcoma virus (RSV)-transformation by herbimycin A in a temperature-sensitive RSV-infected NRK cell line. Herbimycin reduced the total cellular phosphotyrosine level to 10% of the control value. Intracellular p60^src kinase activity was reduced significantly within 3 h of herbimycin treatment, but recovered to approximately 50% of the control within 24 h, and the kinetics paralleled the decrease of the phosphorylation of a cellular target p36. Partial proteolytic phosphopeptide analysis of p60^src revealed decreased phosphorylation of tyrosine 416 in the C-terminal half. Analysis of the steady state level of p60^src indicated 30% decrease in src protein. Measurement of the rates of p60^src synthesis and degradation showed that the decrease in the level was due to the accelerated degradation of src protein. Cycloheximide blocked this enhanced turnover of p60^src, but did not block the herbimycin-induced inactivation of p60^src kinase. Subcellular distribution and myristoylation of p60^src protein were not altered. These results support the idea that RSV transformation is associated with elevated phosphotyrosine levels and indicate that inhibition of src kinase activity can reverse RSV-transformation by reducing cellular phosphotyrosine content.

¹ This work was supported in part by a Grant-in-Aid for Cancer Research from the Japanese Ministry of Education, Science, and Culture.

² To whom requests for reprints should be addressed.

Received 6/ 6/88. Revised 10/17/88. Accepted 11/ 7/88.

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