BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons.
The Bcl-2 family of proteins are key regulators of programmed cell death. A distinct subfamily of BH3-only molecules has been identified, but their exact mechanism of action remains unclear. Here we show that the BH3-only Bcl-2 family members, Dp5/Hrk and Bim, are induced upstream of the Bax checkpoint in neuronal apoptosis in a manner that shows significant dependence on JNK signaling. We also show that Dp5 and other BH3-only proteins kill cerebellar granule neurons in a Bax-dependent manner. These studies demonstrate that BH3-only members do not act independently in their proapoptotic activities but rather require the action of multidomain proapoptotic Bcl-2 family members to produce cell death.
Harris
C A
CA
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Johnson
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EM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D017931:DNA Primers; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D009479:Neuropeptides / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; C494828:Bax protein, rat; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D002352:Carrier Proteins; D017931:DNA Primers; C107631:Hrk protein, mouse; C484585:Hrk protein, rat; D008565:Membrane Proteins; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases