Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-Ras-transformed Rat-1 cells, but not in untransformed cells
| Autor: | G L, James, M S, Brown, M H, Cobb, J L, Goldstein |
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| Rok vydání: | 1994 |
| Předmět: |
MAP Kinase Kinase 2
MAP Kinase Kinase 1 Protein Prenylation In Vitro Techniques Oncogene Protein p21(ras) Protein Serine-Threonine Kinases Transfection Cell Line Proto-Oncogene Proteins p21(ras) Benzodiazepines Proto-Oncogene Proteins Animals Phosphorylation Cells Cultured Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase 3 Epidermal Growth Factor Protein-Tyrosine Kinases Cell Transformation Viral Rats Enzyme Activation Proto-Oncogene Proteins c-raf Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases Oligopeptides Cell Division Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 269(44) |
| ISSN: | 0021-9258 |
| Popis: | A benzodiazepine peptidomimetic, BZA-5B, inhibits farnesylation of H-Ras and normalizes the morphology of Rat-1 cells transformed with H-RasV12 at concentrations that do not affect the growth of untransformed Rat-1 cells. In the current experiments, we show that BZA-5B decreases the active forms of enzymes in the mitogen-activated protein (MAP) kinase signaling cascade, including Raf, MAP kinase kinase (MEK), and MAP kinase, in cells transformed with H-RasV12. BZA-5B had no effect on these enzymes in cells transformed with H-RasV12,L189, which is geranylgeranylated rather than farnesylated. In cells transformed with H-RasV12, BZA-5B reduced the activities of enzymes in the MAP kinase pathway at concentrations that only partially blocked farnesylation of H-RasV12, suggesting that nonfarnesylated H-RasV12 is a dominant inhibitor of the action of farnesylated H-RasV12 in the BZA-5B treated cells. In untransformed Rat-1 cells, BZA-5B did not inhibit MAP kinase activity nor did it prevent the acute activation triggered by epidermal growth factor, even though farnesylated endogenous H-Ras was no longer detectable. These data raise the possibility that untransformed cells contain a form of Ras (K-Ras or N-Ras) whose prenylation is not inhibited by BZA-5B, thus allowing them to resist the effects of BZA-5B. |
| Databáze: | OpenAIRE |
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