Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons

Shoshona S. Le, F. Alexandra Loucks, Hiroshi Udo, Sarah Richardson-Burns, Reid A. Phelps, Ron J. Bouchard, Holger Barth, Klaus Aktories, Kenneth L. Tyler, Eric R. Kandel, Kim A. Heidenreich, Daniel A. Linseman

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1025-1039
Number of pages15
JournalJournal of Neurochemistry
Volume94
Issue number4
DOIs
Publication statusPublished - Aug 1 2005

Fingerprint

GTP Phosphohydrolases
Integrins
Neurons
Chemical activation
rho GTP-Binding Proteins
Protein Kinase Inhibitors
Apoptosis
Intercellular Signaling Peptides and Proteins
cdc42 GTP-Binding Protein
rhoA GTP-Binding Protein
Caspase 9
JNK Mitogen-Activated Protein Kinases
Corrosion inhibitors
p38 Mitogen-Activated Protein Kinases
Cell death
Caspases
Guanosine Triphosphate
Cytochromes c
Transducers
Caspase 3

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Le, S. S., Loucks, F. A., Udo, H., Richardson-Burns, S., Phelps, R. A., Bouchard, R. J., ... 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), 1025-1039. https://doi.org/10.1111/j.1471-4159.2005.03252.x

Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. / 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.

In: Journal of Neurochemistry, Vol. 94, No. 4, 01.08.2005, p. 1025-1039.

Research output: Contribution to journalArticle

Le, SS, Loucks, FA, Udo, H, Richardson-Burns, S, Phelps, RA, Bouchard, RJ, Barth, H, Aktories, K, Tyler, KL, Kandel, ER, Heidenreich, KA & Linseman, DA 2005, '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, pp. 1025-1039. https://doi.org/10.1111/j.1471-4159.2005.03252.x
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. / Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. In: Journal of Neurochemistry. 2005 ; Vol. 94, No. 4. pp. 1025-1039.
@article{f80fffd8a48b4cc6ab08b1ca7f370c6e,
title = "Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons",
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.",
author = "Le, {Shoshona S.} and Loucks, {F. Alexandra} and Hiroshi Udo and Sarah Richardson-Burns and Phelps, {Reid A.} and Bouchard, {Ron J.} and Holger Barth and Klaus Aktories and Tyler, {Kenneth L.} and Kandel, {Eric R.} and Heidenreich, {Kim A.} and Linseman, {Daniel A.}",
year = "2005",
month = "8",
day = "1",
doi = "10.1111/j.1471-4159.2005.03252.x",
language = "English",
volume = "94",
pages = "1025--1039",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "4",

}

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 - 2005/8/1

Y1 - 2005/8/1

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=23844468392&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23844468392&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2005.03252.x

DO - 10.1111/j.1471-4159.2005.03252.x

M3 - Article

C2 - 16092944

AN - SCOPUS:23844468392

VL - 94

SP - 1025

EP - 1039

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 4

ER -