Ribavirin-induced resistance to heat shock, inhibition of the Ras-Raf-1 pathway and arrest in G(1).
Ribavirin [1-(beta-D-ribofuranosyl)1,2,4-triazole-3-carboxamide (virazole)], a specific inhibitor of inositide 5'-monophosphate dehydrogenase (IMPDH), induces a strong depletion of GTP pools in IGR39 cells. After a 3-day treatment, the cell cycle was reversibly arrested in G(0)/G(1), suggesting the involvement of GTP in the cell cycle process. The reduction of the GTP cell content modified the appearance of the microtubule network, as examined using immunofluorescence. However, the dynamics of repolymerisation were not altered. When arrested in G(0)/G(1), cells displayed a surprising resistance to a 3-h period of heat shock at 45 degrees C. Considering the lack of coimmunoprecipitation of p21ras with Raf-1, the reduction of the level of GTP-associated p21ras and the decrease of the activation of the extracellular signal-regulated protein kinases (ERK), also known as mitogen-activated protein (MAP) kinase, in ribavirin-treated cells, we suggest a possible relationship between the expression of heat-shock proteins and the change, in GTP-depleted cells, of the regulation of Raf kinase by ras protein.
Vallée
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Biochimie Cellulaire, UPRES-A 6032 CNRS, Faculté de Pharmacie, 27 Bd Jean Moulin, F-13385 Cedex 5, Marseille, France.
Fouchier
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F
Braguer
D
D
Marvaldi
J
J
Champion
S
S
D000963:Antimetabolites / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D006160:Guanosine Triphosphate / Q000032:analysis; D006360:Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000963:Antimetabolites; D006360:Heat-Shock Proteins; D012254:Ribavirin; D006160:Guanosine Triphosphate; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins