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 transduction pathway of the tumor promoter TPA in 3T3-L1 cells. Compounds which act on microtubules (vinblastine sulfate) and microfilaments (cytochalasin 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 specific and apparently exert their regulatory action distal to activation of 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 decarboxylase). c-jun mRNA levels are not modulated during the action of cytoskeletal disrupting drugs on TPA-mediated mitogenesis, whereas c-myc and c-fos mRNA levels are similarly enhanced. Expression of ornithine decarboxylase mRNA and protein is increased by vinblastine sulfate but decreased by cytochalasin B in TPA treated cells. These data indicate that changes in cytoskeletal organization may play a role in regulating the levels of an enzyme critical for DNA synthesis.
Pavlath
G K
GK
Department of Molecular and Cellular Biology, University of Arizona, Tucson 85721.
Shimizu
Y
Y
Shimizu
N
N
D016475:3T3 Cells; D000818:Animals; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D051379:Mice; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
D003571:Cytochalasin B; D014747:Vinblastine; D004247:DNA; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate