Mechanism underlying cytotoxicity of thialysine, lysine analog, toward human acute leukemia Jurkat T cells |
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Authors: | Jun Do Youn Rue Seok Woo Han Kyu Hyun Taub Dennis Lee Young Sup Bae Young Seuk Kim Young Ho |
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Affiliation: | Laboratory of Immunobiology, Department of Microbiology, College of Natural Sciences, Kyungpook National University, 702-701 Taegu, South Korea. |
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Abstract: | We first report the mechanism for the inhibitory effect of the lysine analog, thialysine on human acute leukemia Jurkat T cells. When Jurkat T cells were treated with thialysine (0.32-2.5 mM), apoptotic cell death along with several biochemical events such as mitochondrial cytochrome c release, caspase-9 activation, caspase-3 activation, degradation of poly (ADP-ribose) polymerase, and DNA fragmentation was induced in a dose- and time-dependent manner. However, these thialysine-induced apoptotic events were significantly abrogated by an ectopic expression of Bcl-xL, which is known to block mitochondrial cytochrome c release. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, also suppressed thialysine-induced apoptotic events. Comparison of the thialysine-induced alterations in the cell cycle distribution between Jurkat T cells transfected with Bcl-xL gene (J/Bcl-xL) and Jurkat T cells transfected with vector (J/Neo) revealed that the apoptotic cells were mainly derived from the cells accumulated in S and G2/M phases following thialysine treatment. The interruption of cell cycle progression in the presence of thialysine was accompanied by a significant decline in the protein level of cdk4, cdk6, cdc2, cyclin A, cyclin B1, and cyclin E. These results demonstrate that the cytotoxic activity of thialysine toward Jurkat T cells is attributable to not only apoptotic cell death mediated by a mitochondria-dependent death signaling pathway, but also interruption of cell cycle progression by a massive down-regulation in the level of cdks and cyclins. |
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Keywords: | PARP, poly (ADP-ribose) polymerase FasL, Fas ligand FBS, fetal bovine serum 2-ME, β-mercaptoethanol MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide PMSF, phenylmethylsulfonyl fluoride MOPS, 3-(N-morpholino)propanesulfonic acid MES, 2-(N-morpholino)ethanesulfonic acid kDa, kilodalton cdk, cyclin-dependent kinase Rb, retinoblastoma protein |
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