tailieunhanh - Báo cáo khoa học: Ionizing radiation utilizes c-Jun N-terminal kinase for amplification of mitochondrial apoptotic cell death in human cervical cancer cells

Exposure of cells to ionizing radiation induces activation of multiple signal-ing pathways that play a critical role in controlling cell death. However, the basis for linkage between signaling pathways and the cell-death machin-ery in response to ionizing radiation remains unclear. | ễFEBS Journal Ionizing radiation utilizes c-Jun N-terminal kinase for amplification of mitochondrial apoptotic cell death in human cervical cancer cells Min-Jung Kim1 Kee-Ho Lee2 and Su-Jae Lee1 1 Laboratory of Molecular Biochemistry Department of Chemistry Hanyang University Seoul Korea 2 Division of Radiation Cancer Biology Korea Institute of Radiologicaland MedicalSciences Seoul Korea Keywords Bax and Bak activation Bcl-2 phosphorylation Fas expression ionizing radiation JNK Correspondence . Lee Laboratory of Molecular Biochemistry Department of Chemistry Hanyang University 17 Haengdang-Dong Seongdong-Ku Seoul133 791 Korea Fax 82 2 2299 0762 Tel 82 2 2220 2557 E-mail sj0420@ Received 24 October 2007 revised 20 February 2008 accepted 27 February 2008 doi Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play a critical role in controlling cell death. However the basis for linkage between signaling pathways and the cell-death machinery in response to ionizing radiation remains unclear. Here we demonstrate that activation of c-Jun N-terminal kinase JNK is critical for amplification of mitochondrial cell death in human cervical cancer cells. Exposure of HeLa cells to radiation induced loss of mitochondrial membrane potential release of cytochrome c and apoptosis inducing factor AIF from mitochondria and apoptotic cell death. Radiation also induced transcriptional upregulation of Fas caspase-8 activation Bax and Bak activation and phosphorylation and downregulation of Bcl-2. Inhibition of caspase-8 attenuated Bax and Bak activation but did not affect phosphorylation and downregulation of Bcl-2. Expression of a mutant form of Bcl-2 S70A-Bcl-2 completely attenuated radiation-induced Bcl-2 downregulation. Interestingly inhibition of JNK clearly attenuated radiation-induced Bax and Bak activation and Bcl-2 phosphorylation as well as Fas expression. In addition dominant-negative