Morphology of ras-transformed cells becomes apparently normal again with tyrosine kinase inhibitors without a decrease in the ras-GTP complex.
Radicicol, an inhibitor of protein-tyrosine kinase, was found to cause morphological reversion of v-Ha-ras-transformed NIH3T3 fibroblasts and T24 human urinary bladder carcinoma cells that contain an activated ras mutation. The network of actin stress fibers was restored during the treatment with radicicol. A similar morphological change was observed with another protein-tyrosine kinase inhibitor, herbimycin A. Radicicol did not cause any changes in the proportion of the active GTP binding form of p21ras or its subcellular localization. These results rule out the possibility that the morphological reversion by radicicol is due to direct or indirect inhibition of the p21ras function. Cycloheximide and actinomycin D inhibited the morphological change by radicicol, suggesting that the induced transcription of a gene(s) followed by de novo protein synthesis is required for suppression of the transformed phenotype in ras-transformed cells by tyrosine kinase inhibitors.
Department of Biotechnology, University of Tokyo.
H J
HJ
Kwon
M
M
Yoshida
K
K
Muroya
S
S
Hattori
E
E
Nishida
Y
Y
Fukui
T
T
Beppu
S
S
Horinouchi
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011905:Genes, ras; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D051379:Mice; D017354:Point Mutation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000235:genetics*; D011809:Quinones / Q000494:pharmacology; D012016:Reference Values; D017828:Rifabutin / Q000031:analogs & derivatives; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D006160:Guanosine Triphosphate; D011505:Protein-Tyrosine Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C035359:monorden