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Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons.
J Neurochem. 2005 Aug; 94(4):1025-39.JN

Abstract

Rho GTPases are key transducers of integrin/extracellular matrix and growth factor signaling. Although integrin-mediated adhesion and trophic support suppress neuronal apoptosis, the role of Rho GTPases in neuronal survival is unclear. Here, we have identified Rac as a critical pro-survival GTPase in cerebellar granule neurons (CGNs) and elucidated a death pathway triggered by its inactivation. GTP-loading of Rac1 was maintained in CGNs by integrin-mediated (RGD-dependent) cell attachment and trophic support. Clostridium difficile toxin B (ToxB), a specific Rho family inhibitor, induced a selective caspase-mediated degradation of Rac1 without affecting RhoA or Cdc42 protein levels. Both ToxB and dominant-negative N17Rac1 elicited CGN apoptosis, characterized by cytochrome c release and activation of caspase-9 and -3, whereas dominant-negative N19RhoA or N17Cdc42 did not cause significant cell death. ToxB stimulated mitochondrial translocation and conformational activation of Bax, c-Jun activation, and induction of the BH3-only protein Bim. Similarly, c-Jun activation and Bim induction were observed with N17Rac1. A c-jun N-terminal protein kinase (JNK)/p38 inhibitor, SB203580, and a JNK-specific inhibitor, SP600125, significantly decreased ToxB-induced Bim expression and blunted each subsequent step of the apoptotic cascade. These results indicate that Rac acts downstream of integrins and growth factors to promote neuronal survival by repressing c-Jun/Bim-mediated mitochondrial apoptosis.

Authors+Show Affiliations

Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16092944

Citation

Le, Shoshona S., et al. "Inhibition of Rac GTPase Triggers a c-Jun- and Bim-dependent Mitochondrial Apoptotic Cascade in Cerebellar Granule Neurons." Journal of Neurochemistry, vol. 94, no. 4, 2005, pp. 1025-39.
Le SS, Loucks FA, Udo H, et al. Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. J Neurochem. 2005;94(4):1025-39.
Le, S. S., Loucks, F. A., Udo, H., Richardson-Burns, S., Phelps, R. A., Bouchard, R. J., Barth, H., Aktories, K., Tyler, K. L., Kandel, E. R., Heidenreich, K. A., & Linseman, D. A. (2005). Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. Journal of Neurochemistry, 94(4), 1025-39.
Le SS, et al. Inhibition of Rac GTPase Triggers a c-Jun- and Bim-dependent Mitochondrial Apoptotic Cascade in Cerebellar Granule Neurons. J Neurochem. 2005;94(4):1025-39. PubMed PMID: 16092944.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. AU - Le,Shoshona S, AU - Loucks,F Alexandra, AU - Udo,Hiroshi, AU - Richardson-Burns,Sarah, AU - Phelps,Reid A, AU - Bouchard,Ron J, AU - Barth,Holger, AU - Aktories,Klaus, AU - Tyler,Kenneth L, AU - Kandel,Eric R, AU - Heidenreich,Kim A, AU - Linseman,Daniel A, PY - 2005/8/12/pubmed PY - 2005/9/28/medline PY - 2005/8/12/entrez SP - 1025 EP - 39 JF - Journal of neurochemistry JO - J Neurochem VL - 94 IS - 4 N2 - Rho GTPases are key transducers of integrin/extracellular matrix and growth factor signaling. Although integrin-mediated adhesion and trophic support suppress neuronal apoptosis, the role of Rho GTPases in neuronal survival is unclear. Here, we have identified Rac as a critical pro-survival GTPase in cerebellar granule neurons (CGNs) and elucidated a death pathway triggered by its inactivation. GTP-loading of Rac1 was maintained in CGNs by integrin-mediated (RGD-dependent) cell attachment and trophic support. Clostridium difficile toxin B (ToxB), a specific Rho family inhibitor, induced a selective caspase-mediated degradation of Rac1 without affecting RhoA or Cdc42 protein levels. Both ToxB and dominant-negative N17Rac1 elicited CGN apoptosis, characterized by cytochrome c release and activation of caspase-9 and -3, whereas dominant-negative N19RhoA or N17Cdc42 did not cause significant cell death. ToxB stimulated mitochondrial translocation and conformational activation of Bax, c-Jun activation, and induction of the BH3-only protein Bim. Similarly, c-Jun activation and Bim induction were observed with N17Rac1. A c-jun N-terminal protein kinase (JNK)/p38 inhibitor, SB203580, and a JNK-specific inhibitor, SP600125, significantly decreased ToxB-induced Bim expression and blunted each subsequent step of the apoptotic cascade. These results indicate that Rac acts downstream of integrins and growth factors to promote neuronal survival by repressing c-Jun/Bim-mediated mitochondrial apoptosis. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/16092944/Inhibition_of_Rac_GTPase_triggers_a_c_Jun__and_Bim_dependent_mitochondrial_apoptotic_cascade_in_cerebellar_granule_neurons_ L2 - https://doi.org/10.1111/j.1471-4159.2005.03252.x DB - PRIME DP - Unbound Medicine ER -