Cyclin-dependent protein kinase 2 activity is required for mitochondrial translocation of Bax and disruption of mitochondrial transmembrane potential during etoposide-induced apoptosis |
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Authors: | Joon-Seok Choi Soona Shin Ying Hua Jin Hyungshin Yim Kyo-Tan Koo Kwang-Hoon Chun You-Take Oh Won Hee Lee Seung-Ki Lee |
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Institution: | (1) Division of Pharmaceutical Biosciences, College of Pharmacy and The Research Institute for Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Korea;(2) Division of Pharmaceutical Biosciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea;(3) College of Life Science, Jilin University, Changchun, 130012, China |
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Abstract: | Previous studies have suggested that upregulation of Cyclin A-dependent protein kinase 2 (Cdk2) activity is an essential event
in apoptotic progression and the mitochondrial permeability transition in human cancer cells. Here, we show that upregulated
Cyclin A/Cdk2 activity precedes the proteolytic cleavage of PARP and is correlated with the mitochondrial translocation of
Bax and the loss of mitochondrial transmembrane potential (Δψm) during etoposide-induced apoptosis in human cervical adenocarcinoma (HeLa) cells. Etoposide-induced apoptotic cell death
is efficiently prevented in cells that overexpress a dominant negative mutant of Cdk2 (Cdk2-dn) or p21WAF1/CIP1, a specific Cdk inhibitor. Conversely, apoptotic cell death is promoted in Cyclin A-expressing cells. Disruption of the mitochondrial
transmembrane potential in etoposide-induced cells is prevented in cells that overexpress Cdk2-dn or p21WAF1/CIP1, while this transition is prominently promoted in Cyclin A-expressing cells. We screened for mitochondrial Cdk2 targets in
the etoposide-induced cells and found that the mitochondrial level of Bax is elevated by more than three fold in etoposide-treated
cells and this elevation is effectively prevented in cells expressing Cdk2-dn under the same conditions. Thus, we suggest
that Cdk2 activity is involved in the mitochondrial translocation of Bax, which plays an important role in the mitochondrial
membrane permeability transition during apoptotic progression. |
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Keywords: | Apoptosis Bax Cdk2 activity Mitochondrial membrane potential Mitochondrial translocation |
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