Activation of Lck is critically required for sphingosine-induced conformational activation of Bak and mitochondrial cell death |
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Authors: | Kim Min-Jung Park Moon-Taek Yoon Chang-Hwan Byun Joo-Yun Lee Su-Jae |
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Institution: | Laboratory of Molecular Biochemistry, Department of Chemistry, Hanyang University, 17 Haengdang-Dong, Seongong-Ku, Seoul 133-791, Republic of Korea |
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Abstract: | Despite extensive investigation, the molecular mechanism of anticancer activity of sphingolipid metabolites remains to be clarified. Here we demonstrate that sphingosine induces mitochondrial cell death via Lck-mediated conformational activation of Bak in Jurkat T cell lymphoma. Treatment of cells with sphingosine rapidly induced mitochondrial membrane potential loss, cytochrome c release from mitochondria, and apoptotic cell death. Sphingosine also induced conformational activation of Bak, but not Bax. siRNA targeting of Bak effectively attenuated sphingosine-induced mitochondrial cell death, indicating that Bak is involved in sphingosine-induced mitochondrial cell death. Sphingosine also induced activation of tyrosine kinase Lck. Inhibition of Lck by treatment of PP2, a Lck inhibitor or siRNA targeting of Lck suppressed sphingosine-induced conformational activation and oligomerization of Bak, mitochondrial membrane potential loss, and apoptotic cell death, implying that activation of Lck is critically required for sphingosine-induced conformational activation of Bak and mitochondrial cell death. The results elucidated in this study provide a novel cellular mechanism for the anticancer activity of sphingolipid metabolites. |
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Keywords: | Lck lymphocyte-specific protein tyrosine kinase DiOC6(3) 3 3&prime dihexyloxacarbocyanine iodide TRAIL tumor necrosis factor-related apoptosis-inducing ligand |
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