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Src Tyrosine Kinase Mediates Stimulation of Raf-1 and Mitogen-activated Protein Kinase by the Tumor Promoter Thapsigargin¹

The Ben May Institute for Cancer Research and Departments of Pharmacological and Physiological Sciences [T-S. O. C., I. G., M. R. R.] and Pediatrics [M. A., M. B. H.], University of Chicago, Chicago, Illinois 60637

Thapsigargin is a non-phorbol ester-type tumor promoter that elevates the intracellular Ca²⁺ (Ca_i²⁺) levels by blocking the microsomal Ca²⁺ ATPase. At present, the consequence of this Ca_i²⁺ increase and the nature of the tumorigenicity of thapsigargin still remain to be elucidated. Previously, we demonstrated that thapsigargin activates the mitogen-activated protein (MAP) kinase via Ca_i²⁺ but independently of protein kinase C or Ca²⁺ influx. Here, we show that thapsigargin also rapidly stimulates the Src tyrosine kinase. Transfection of a v-Src gene into a hippocampal cell line (H19-7) renders a constitutive activation of MAP kinase, whereas transfection of a kinase-deficient Src mutant blocks the activation by thapsigargin, suggesting that Src is required for the thapsigargin-induced MAP kinase activation. Cotransfection of a dominant-inhibitory Raf-1 and the v-Src genes into H19-7 cells results in an inhibition of the otherwise constitutively elevated MAP kinase activity, suggesting that Raf-1 is required for the Src-dependent activation of MAP kinase. Similarly, in the LA-90 cells, expression of a temperature-sensitive allele of v-Src constitutively activates Raf-1 and MAP kinase, whereas expression of a dominant-inhibitory Raf-1 mutant abolishes the MAP kinase activation induced by either v-Src or thapsigargin treatment. Together, these results suggest that thapsigargin stimulates MAP kinase signaling via Src and Raf-1. The activation of this Src-MAP kinase pathway suggests a biochemical mechanism for the tumorigenic nature of thapsigargin.

¹ This work was supported by NIH Grant CA 35541 (to M. R. R.) and a gift from the Cornelius Crane Foundation.

² Current address: Synthélabo Research, Bagneux 92225, France.

³ To whom requests for reprints should be addressed, at the Ben May Institute for Cancer Research, MC 6027, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: (773) 702-1857; Fax: (773) 702-4634 or 6260; E-mail: mrosner@ben-may.bsd.uchicago.edu.

Received 1/13/97. Accepted 5/28/97.

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