Intrinsic and extrinsic pathway signaling during neuronal apoptosis: lessons from the analysis of mutant mice.
Trophic factor deprivation (TFD)-induced apoptosis in sympathetic neurons requires macromolecular synthesis-dependent BAX translocation, cytochrome c (cyt c) release, and caspase activation. Here, we report the contributions of other intrinsic and extrinsic pathway signals to these processes. Sympathetic neurons expressed all antiapoptotic BCL-2 proteins examined, yet expressed only certain BH3-only and multidomain proapoptotic BCL-2 family members. All coexpressed proapoptotic proteins did not, however, exhibit functional redundancy or compensatory expression, at least in the Bax-/-, Bak-/-, Bim-/-, Bid-/-, and Bad-/- neurons examined. Although the subcellular distribution or posttranslational modification of certain BCL-2 proteins changed with TFD, neither transcriptional nor posttranslational mechanisms regulated the expression or subcellular localization of BID, BAD, or BAK in this paradigm. Despite modest induction of Fas and FasL expression, Fas-mediated signaling did not contribute to TFD-induced apoptosis in sympathetic neurons. Similar findings were obtained with K+ withdrawal-induced apoptosis in cerebellar granule neurons, a model for activity-dependent neuronal survival in the CNS. Thus, expression alone does not guarantee functional redundancy (or compensation) among BCL-2 family members, and, at least in some cells, extrinsic pathway signaling and certain BH3-only proteins (i.e., BID and BAD) do not contribute to BAX-dependent cyt c release or apoptosis caused by TFD.
Putcha
Girish V
GV
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Harris
Charles A
CA
Moulder
Krista L
KL
Easton
Rachael M
RM
Thompson
Craig B
CB
Johnson
Eugene M
EM
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000166:cytology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494820:Bad protein, mouse; C494821:Bad protein, rat; C494773:Bak1 protein, mouse; C494774:Bak1 protein, rat; C494815:Bid protein, mouse; C494816:Bid protein, rat; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein