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- Title
Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons.
- Authors
Le, Shoshona S.; Loucks, F. Alexandra; Udo, Hiroshi; Richardson-Burns, Sarah; Phelps, Reid A.; Bouchard, Ron J.; Barth, Holger; Aktories, Klaus; Tyler, Kenneth L.; Kandel, Eric R.; Heidenreich, Kim A.; Linseman, Daniel A.
- 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.
- Subjects
GUANOSINE triphosphatase; TRANSDUCERS; EXTRACELLULAR matrix; GROWTH factors; APOPTOSIS; RHO GTPases; CYTOCHROME c; NEURONS
- Publication
Journal of Neurochemistry, 2005, Vol 94, Issue 4, p1025
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2005.03252.x