CYTOSKELETAL ACTIVE-DRUGS MODULATE SIGNAL-TRANSDUCTION IN THE PROTEIN-KINASE-C PATHWAY

The cytoskeletal network of cells is postulated to play a role in the signal transduction pathways of growth promoting stimuli. We show here that cytoskeletal active drugs modulate the mitogenic signal transduc tion pathway of the tumor promoter TPA in 3T3-L1 cells. Compounds whic h act on microtubules (vinblastine sulfate) and microfilaments (cytoch alasin B) have opposite effects on DNA synthesis. Vinblastine sulfate leads to stimulation, whereas cytochalasin B causes potent inhibition of DNA synthesis in response to TPA. These drugs are cell cycle specif ic and apparently exert their regulatory action distal to activation o f protein kinase C by TPA. The expression of four genes necessary for DNA synthesis in response to tumor promoters was examined: two nuclear proto-oncogenes (c-myc and c-fos), a transcription factor (c-jun/AP-1 ) and a key enzyme involved in polyamine synthesis (ornithine decarbox ylase). c-jun mRNA levels are not modulated during the action of cytos keletal disrupting drugs on TPA-mediated mitogenesis, whereas c-myc an d c-fos mRNA levels are similarly enhanced. Expression of ornithine de carboxylase mRNA and protein is increased by vinblastine sulfate but d ecreased by cytochalasin B in TPA treated cells. These data indicate t hat changes in cytoskeletal organization may play a role in regulating the levels of an enzyme critical for DNA synthesis.