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Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways Zhang L; Lopez H; George NM; Liu X; Pang X; Luo XCell Death Differ 2011[May]; 18 (5): 864-73The 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 TNF-related apoptosis-inducing ligand (TRAIL), endoplasmic reticulum (ER) stress, and proteasome inhibition. Among the 10 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.|*Apoptosis[MESH]|Apoptosis Regulatory Proteins/genetics/metabolism[MESH]|BH3 Interacting Domain Death Agonist Protein/genetics/metabolism[MESH]|Bcl-2-Like Protein 11[MESH]|Endoplasmic Reticulum/physiology[MESH]|HeLa Cells[MESH]|Humans[MESH]|Leupeptins/pharmacology[MESH]|Membrane Proteins/genetics/metabolism[MESH]|Myeloid Cell Leukemia Sequence 1 Protein[MESH]|Proteasome Inhibitors[MESH]|Protein Binding[MESH]|Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism[MESH]|Proto-Oncogene Proteins/genetics/metabolism[MESH]|RNA Interference[MESH]|Stress, Physiological[MESH]|TNF-Related Apoptosis-Inducing Ligand/pharmacology/physiology[MESH]|Thapsigargin/pharmacology[MESH]|bcl-2 Homologous Antagonist-Killer Protein/genetics/metabolism[MESH]|bcl-2-Associated X Protein/genetics/metabolism[MESH]|bcl-Associated Death Protein/genetics/metabolism[MESH]|bcl-X Protein/metabolism[MESH] |
