Activation of Lck is critically required for sphingosine-induced conformational activation of Bak and mitochondrial cell death
- Authors
- Kim, Min-Jung; Park, Moon-Taek; Yoon, Chang-Hwan; Byun, Joo-Yun; Lee, Su-Jae
- Issue Date
- May-2008
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Keywords
- sphingolipid metabolites; sphingosine-induced mitochondrial cell death; Bak-dependent cell death by sphingosine; Lck-mediated conformational activation of; Bak
- Citation
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.370, no.2, pp.353 - 358
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
- Volume
- 370
- Number
- 2
- Start Page
- 353
- End Page
- 358
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/172081
- DOI
- 10.1016/j.bbrc.2008.03.084
- ISSN
- 0006-291X
- 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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