| Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways. | |
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MedLine Citation:
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PMID: 21113147 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 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. |
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Authors:
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L Zhang; H Lopez; N M George; X Liu; X Pang; X Luo |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-11-26 |
Journal Detail:
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Title: Cell death and differentiation Volume: 18 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-04-11 Completed Date: 2011-09-23 Revised Date: 2012-10-15 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 864-73 Citation Subset: IM |
Affiliation:
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Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis* Apoptosis Regulatory Proteins / genetics, metabolism BH3 Interacting Domain Death Agonist Protein / genetics, metabolism Endoplasmic Reticulum / physiology HeLa Cells Humans Leupeptins / pharmacology Membrane Proteins / genetics, metabolism Proteasome Endopeptidase Complex / antagonists & inhibitors Protein Binding Proto-Oncogene Proteins / genetics, metabolism Proto-Oncogene Proteins c-bcl-2 / genetics, metabolism* RNA Interference Stress, Physiological TNF-Related Apoptosis-Inducing Ligand / pharmacology, physiology Thapsigargin / pharmacology bcl-2 Homologous Antagonist-Killer Protein / genetics, metabolism bcl-2-Associated X Protein / genetics, metabolism bcl-Associated Death Protein / genetics, metabolism bcl-X Protein / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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GM76237/GM/NIGMS NIH HHS; GM76237-04S1/GM/NIGMS NIH HHS; R01 GM076237-04S1/GM/NIGMS NIH HHS; R01 GM076237-05/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/BAD protein, human; 0/BAK1 protein, human; 0/BAX protein, human; 0/BBC3 protein, human; 0/BCL2L1 protein, human; 0/BCL2L2 protein, human; 0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/BNIP3 protein, human; 0/Bcl-2-like protein 11; 0/Leupeptins; 0/Membrane Proteins; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; 0/bcl-Associated Death Protein; 0/bcl-X Protein; 0/myeloid cell leukemia sequence 1 protein; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 67526-95-8/Thapsigargin; EC 3.4.25.1/Proteasome Endopeptidase Complex |
| Comments/Corrections | |
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