Title

Signal transducer and activator of transcription-5 mediates neuronal apoptosis induced by inhibition of Rac GTPase activity.

Authors

Trisha R Stankiewicz, University of Denver
F Alexandra Loucks, Veterans Affairs Medical Center, Denver,
Emily K Schroeder, Veterans Affairs Medical Center, Denver,
Marja T Nevalainen, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Kenneth L Tyler, University of Colorado Denver
Klaus Aktories, Albert-Ludwigs-Universität Freiburg
Ron J Bouchard, Veterans Affairs Medical Center, Denver
Daniel A Linseman, Veterans Affairs Medical Center, Denver

Document Type

Article

Publication Date

5-11-2012

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Journal of Biological Chemistry

Volume 287, Issue 20, May 2012, Pages 16835-16848.

The published version is available at DOI: 10.1074/jbc.M111.302166. Copyright © American Society for Biochemistry and Molecular Biology

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.

Recommended Citation

Stankiewicz, Trisha R; Loucks, F Alexandra; Schroeder, Emily K; Nevalainen, Marja T; Tyler, Kenneth L; Aktories, Klaus; Bouchard, Ron J; and Linseman, Daniel A, "Signal transducer and activator of transcription-5 mediates neuronal apoptosis induced by inhibition of Rac GTPase activity." (2012). Department of Cancer Biology Faculty Papers. Paper 28.
https://jdc.jefferson.edu/cbfp/28

PubMed ID

22378792