PMID:11980919

Citation	Putcha, GV, Harris, CA, Moulder, KL, Easton, RM, Thompson, CB and Johnson, EM Jr (2002) Intrinsic and extrinsic pathway signaling during neuronal apoptosis: lessons from the analysis of mutant mice. J. Cell Biol. 157:441-53
Abstract	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.
Links	PubMed PMC2173286 Online version:10.1083/jcb.200110108
Keywords	Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cells, Cultured; Cytochrome c Group/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mutation; Nerve Growth Factors/metabolism; Neurons/cytology; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Rats; Signal Transduction; Sympathetic Nervous System/cytology; bcl-2 Homologous Antagonist-Killer Protein; bcl-Associated Death Protein
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