Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Signal transducer and activator of transcription-5 mediates neuronal apoptosis induced by inhibition of Rac GTPase activity. J Biol Chem 2012 May 11;287(20):16835-48

Date

03/02/2012

Pubmed ID

22378792

Pubmed Central ID

PMC3351344

DOI

10.1074/jbc.M111.302166

Scopus ID

2-s2.0-84860879228   14 Citations

Abstract

In several neuronal cell types, the small GTPase Rac is essential for survival. We have shown previously that the Rho family GTPase inhibitor Clostridium difficile toxin B (ToxB) induces apoptosis in primary rat cerebellar granule neurons (CGNs) principally via inhibition of Rac GTPase function. In the present study, incubation with ToxB activated a proapoptotic Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and a pan-JAK inhibitor protected CGNs from Rac inhibition. STAT1 expression was induced by ToxB; however, CGNs from STAT1 knock-out mice succumbed to ToxB-induced apoptosis as readily as wild-type CGNs. STAT3 displayed enhanced tyrosine phosphorylation following treatment with ToxB, and a reputed inhibitor of STAT3, cucurbitacin (JSI-124), reduced CGN apoptosis. Unexpectedly, JSI-124 failed to block STAT3 phosphorylation, and CGNs were not protected from ToxB by other known STAT3 inhibitors. In contrast, STAT5A tyrosine phosphorylation induced by ToxB was suppressed by JSI-124. In addition, roscovitine similarly inhibited STAT5A phosphorylation and protected CGNs from ToxB-induced apoptosis. Consistent with these results, adenoviral infection with a dominant negative STAT5 mutant, but not wild-type STAT5, significantly decreased ToxB-induced apoptosis of CGNs. Finally, chromatin immunoprecipitation with a STAT5 antibody revealed increased STAT5 binding to the promoter region of prosurvival Bcl-xL. STAT5 was recruited to the Bcl-xL promoter region in a ToxB-dependent manner, and this DNA binding preceded Bcl-xL down-regulation, suggesting transcriptional repression. These data indicate that a novel JAK/STAT5 proapoptotic pathway significantly contributes to neuronal apoptosis induced by the inhibition of Rac GTPase.

Author List

Stankiewicz TR, Loucks FA, Schroeder EK, Nevalainen MT, Tyler KL, Aktories K, Bouchard RJ, Linseman DA

Author

Marja T. Nevalainen MD, PhD Assistant Dean, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Bacterial Proteins
Bacterial Toxins
Cells, Cultured
Cerebellum
Mice
Mice, Knockout
Mutation
Neurons
Phosphorylation
Rats
STAT1 Transcription Factor
STAT3 Transcription Factor
STAT5 Transcription Factor
Signal Transduction
Triterpenes
bcl-X Protein
rac GTP-Binding Proteins
jenkins-FCD Prod-403 0f9a74600e4e79798f8fa6f545ea115f3dd948b2