Molecular Mechanism of JNK/Bim/Bax Apoptotic Pathway Induced by TNF-α in Differentiated PC12 Cells*

Abstract

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-xLin 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 Nave 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.