This work was supported by grants from The Program for Changjiang Scholars and Innovative Research Team in University (IRT0829), The National Natural Science Foundation of China (30870676, 30870658), The Natural Science Foundation of Guangdong Province (7117865) and The Doctoral Research Fund of Guangzhou Medical College (295031)
Alzheimer's disease (AD) is a neurodegenerative disease. Recent years, AD has been found closely related to cell apoptosis. It is reported that the synthesis of excessive tumor necrosis factor-α (TNF-α) has been widely considered as a potential inducer of apoptosis contributing to neurodegenerative disease such as AD. However, the molecular mechanism of TNF-α-mediated apoptosis in neuron remains unclear. The signaling pathways involved in TNF-α-induced apoptosis in living differentiated PC12 cells were investigated by using confocal microscope and FRET (fluorescence resonance energy transfer) technique for the first time. Experimental results show that the TNF-α induced apoptosis in differentiated PC12 cells through "extrinsic" or death receptor-initiated pathway, and the "intrinsic" or mitochondrial pathway. NF-κB can inhibit mitochondrial pathway apoptosis through up-regulation of Bcl-xL by TNF-α induced. Further results show that BimL displaces Bcl-xL in the mitochondria and promotes Bax translocation during TNF-α-induced apoptosis. Furthermore, SP600125 (specific inhibitor of JNK) can inhibit the Bax translocation to mitochondria. Finally, Bax is found to translocate to mitochondria in Naive PC12 cells with co-expressing of GFP-BimL and YFP-Bax. The research demonstrates the important role of BimL, and reveals that BimL activate Bax indirectly during TNF-α-induced apoptosis.
ZHANG Lan, XING Da. Molecular Mechanism of JNK/Bim/Bax Apoptotic Pathway Induced by TNF-α in Differentiated PC12 Cells[J]. Progress in Biochemistry and Biophysics,2010,37(4):370-380
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