Neurites induced by staurosporine in PC12 cells are resistant to colchicine and express high levels of tau proteins.
Staurosporine, a protein kinase inhibitor, induces neurite outgrowth in pheochromocytoma cells and, therefore, may serve as a potential prototype for neurotropic drugs. The principal aim of the present study was to characterize the cytoskeletal properties of neurites induced in pheochromocytoma cells by staurosporine, in comparison to those induced by nerve growth factor, with emphasis on tubulin and tau proteins. Two major findings are described: a) staurosporine rapidly induces outgrowth of neurites that are resistant to colchicine treatment; and b) staurosporine treatment causes a rapid increase in tau protein levels, with a time course similar to the initiation of its neurotropic effects. The following observations exclude tubulin as the cellular target for staurosporine action: a) the level, cellular distribution, and assembly properties of tubulin are not affected by staurosporine treatment; and b) colchicine uptake, its binding to tubulin, and its interference with tubulin polymerization are not changed by staurosporine. On the other hand, staurosporine treatment causes a transient, dose-dependent increase in tau protein levels. This increase, which is already evident after 1 hr, reaches a maximum of 2 to 3 fold after 5 hr of treatment and declines to basal level within the next 10 to 15 hr. The rapid, transient increase of tau protein levels induced by staurosporine is reminiscent of its neurotropic properties. Here we characterize and compare the cytoskeletal properties of neurites induced by treatment with staurosporine and with nerve growth factor, and we offer a mechanistic explanation for the rapid stabilization of staurosporine induced neurites.
Rasouly
D
D
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Rahamim
E
E
Ringel
I
I
Ginzburg
I
I
Muarakata
C
C
Matsuda
Y
Y
Lazarovici
P
P
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D003078:Colchicine / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D051379:Mice; D008855:Microscopy, Electron, Scanning; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000096:biosynthesis*
D000470:Alkaloids; D014404:Tubulin; D016875:tau Proteins; D011493:Protein Kinase C; D019311:Staurosporine; D003078:Colchicine