Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways.
Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways.
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DOI：
10.1038/cdd.2010.152
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发表时间：
2011-05
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
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The BH3-only proteins of the Bcl-2 family are known to mediate mitochondrial dysfunction during apoptosis. However, the identity of the critical BH3-only proteins and the mechanism of their action following treatment by diverse apoptotic stimuli remain to be fully resolved. We therefore used RNAi to screen the entire Bcl-2 family for their involvement in three major apoptotic pathways in HeLa cells. We found that Bcl-xL and Mcl-1 are major inhibitors of apoptosis induced by TRAIL (TNF-related apoptosis-inducing ligand), ER (endoplasmic reticulum) stress, and proteasome inhibition. Among the ten BH3-only proteins, Bid and Noxa were found to be critically involved in TRAIL-induced apoptosis, in which Noxa participates by constitutively binding to Mcl-1. Bim and Noxa were found to be necessary for ER stress-induced apoptosis, in which Noxa assisted Bim function by sequestering Mcl-1 and binding to Bcl-xL. As a critical BH3-only protein, Noxa was strongly upregulated and became associated with both Mcl-1 and Bcl-xL during apoptosis induced by proteasome inhibition. In addition, we found that Noxa became “Mcl-1 free” following treatment by ER stress and proteasome inhibition, but not after TRAIL treatment. These results defined the critical Bcl-2 network during apoptosis and suggested that Noxa participated in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms.
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