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Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl-2/Bcl-x(L) versus induction of the BH3-only protein Bim.
J Neurochem 2005; 94(1):22-36JN

Abstract

Primary cerebellar granule neurons (CGNs) require depolarizing extracellular potassium for their survival. Removal of depolarizing potassium triggers CGN apoptosis that requires induction of Bim, a BH3-only Bcl-2 family member. Bim is classically thought to promote apoptosis by neutralizing pro-survival Bcl-2 proteins. To determine if this is the principal function of Bim in CGNs, we contrasted Bim-mediated apoptosis to neuronal death induced by HA14-1, a BH3-domain mimetic that antagonizes Bcl-2 and Bcl-x(L). HA14-1 elicited CGN apoptosis characterized by caspase 3 and 9 activation, cytochrome c release, conformational activation of Bax, and mitochondrial depolarization. HA14-1 provoked CGN apoptosis in the absence of Bim induction and negative regulators of Bim transcription did not prevent HA14-1-induced cell death. However, the antioxidant glutathione and its precursor, N-acetyl-l-cysteine, suppressed HA14-1-induced apoptosis. Similarly, apoptosis induced by either a structurally distinct Bcl-2/Bcl-x(L) inhibitor (compound 6) or Bcl-2 antisense oligonucleotides was diminished by glutathione. In contrast, antioxidants had no effect on CGN apoptosis provoked by either removal of depolarizing potassium or overexpression of a GFP-Bim fusion protein, two models of Bim-dependent death. These data show that antagonism of Bcl-2/Bcl-x(L) function elicits oxidative stress-dependent CGN apoptosis that is mechanistically distinct from Bim-mediated cell death. These results further indicate that, although Bcl-2/Bcl-x(L) antagonism is sufficient to induce neuronal apoptosis, Bim likely promotes neuronal death by interacting with additional proteins besides Bcl-2/Bcl-x(L).

Authors+Show Affiliations

Neuroscience Program, University of Colorado Health Sciences Center, Denver, Colorado, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15953346

Citation

Zimmermann, Angela K., et al. "Distinct Mechanisms of Neuronal Apoptosis Are Triggered By Antagonism of Bcl-2/Bcl-x(L) Versus Induction of the BH3-only Protein Bim." Journal of Neurochemistry, vol. 94, no. 1, 2005, pp. 22-36.
Zimmermann AK, Loucks FA, Le SS, et al. Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl-2/Bcl-x(L) versus induction of the BH3-only protein Bim. J Neurochem. 2005;94(1):22-36.
Zimmermann, A. K., Loucks, F. A., Le, S. S., Butts, B. D., Florez-McClure, M. L., Bouchard, R. J., ... Linseman, D. A. (2005). Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl-2/Bcl-x(L) versus induction of the BH3-only protein Bim. Journal of Neurochemistry, 94(1), pp. 22-36.
Zimmermann AK, et al. Distinct Mechanisms of Neuronal Apoptosis Are Triggered By Antagonism of Bcl-2/Bcl-x(L) Versus Induction of the BH3-only Protein Bim. J Neurochem. 2005;94(1):22-36. PubMed PMID: 15953346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl-2/Bcl-x(L) versus induction of the BH3-only protein Bim. AU - Zimmermann,Angela K, AU - Loucks,F Alexandra, AU - Le,Shoshona S, AU - Butts,Brent D, AU - Florez-McClure,Maria L, AU - Bouchard,Ron J, AU - Heidenreich,Kim A, AU - Linseman,Daniel A, PY - 2005/6/15/pubmed PY - 2005/8/9/medline PY - 2005/6/15/entrez SP - 22 EP - 36 JF - Journal of neurochemistry JO - J. Neurochem. VL - 94 IS - 1 N2 - Primary cerebellar granule neurons (CGNs) require depolarizing extracellular potassium for their survival. Removal of depolarizing potassium triggers CGN apoptosis that requires induction of Bim, a BH3-only Bcl-2 family member. Bim is classically thought to promote apoptosis by neutralizing pro-survival Bcl-2 proteins. To determine if this is the principal function of Bim in CGNs, we contrasted Bim-mediated apoptosis to neuronal death induced by HA14-1, a BH3-domain mimetic that antagonizes Bcl-2 and Bcl-x(L). HA14-1 elicited CGN apoptosis characterized by caspase 3 and 9 activation, cytochrome c release, conformational activation of Bax, and mitochondrial depolarization. HA14-1 provoked CGN apoptosis in the absence of Bim induction and negative regulators of Bim transcription did not prevent HA14-1-induced cell death. However, the antioxidant glutathione and its precursor, N-acetyl-l-cysteine, suppressed HA14-1-induced apoptosis. Similarly, apoptosis induced by either a structurally distinct Bcl-2/Bcl-x(L) inhibitor (compound 6) or Bcl-2 antisense oligonucleotides was diminished by glutathione. In contrast, antioxidants had no effect on CGN apoptosis provoked by either removal of depolarizing potassium or overexpression of a GFP-Bim fusion protein, two models of Bim-dependent death. These data show that antagonism of Bcl-2/Bcl-x(L) function elicits oxidative stress-dependent CGN apoptosis that is mechanistically distinct from Bim-mediated cell death. These results further indicate that, although Bcl-2/Bcl-x(L) antagonism is sufficient to induce neuronal apoptosis, Bim likely promotes neuronal death by interacting with additional proteins besides Bcl-2/Bcl-x(L). SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15953346/Distinct_mechanisms_of_neuronal_apoptosis_are_triggered_by_antagonism_of_Bcl_2/Bcl_x_L__versus_induction_of_the_BH3_only_protein_Bim_ L2 - https://doi.org/10.1111/j.1471-4159.2005.03156.x DB - PRIME DP - Unbound Medicine ER -