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CRMP5-associated GTPase (CRAG) protein protects neuronal cells against cytotoxicity of expanded polyglutamine protein partially via c-Fos-dependent activator protein-1 activation.

Abstract
We previously demonstrated that CRAM (CRMP5)-associated GTPase (CRAG), a short splicing variant of centaurin-γ3/AGAP3, facilitated degradation of expanded polyglutamine protein (polyQ) via the nuclear ubiquitin-proteasome pathway. Taking advantage of this feature, we also showed that lentivirus-mediated CRAG expression in the Purkinje cells of mice expressing polyQ resulted in clearance of the polyQ aggregates and rescue from ataxia. However, the molecular basis of the function of CRAG in cell survival against polyQ remains unclear. Here we report that CRAG, but not centaurin-γ3, induces transcriptional activation of c-Fos-dependent activator protein-1 (AP-1) via serum response factor (SRF). Mutation analysis indicated that the nuclear localization signal and both the N- and C-terminal regions of CRAG are critical for SRF-dependent c-Fos activation. CRAG knockdown by siRNA or expression of a dominant negative mutant of CRAG significantly attenuated the c-Fos activation triggered by either polyQ or the proteasome inhibitor MG132. Importantly, c-Fos expression partially rescued the enhanced cytotoxicity of CRAG knockdown in polyQ-expressing or MG132-treated cells. Finally, we suggest the possible involvement of CRAG in the sulfiredoxin-mediated antioxidant pathway via AP-1. Taken together, these results demonstrated that CRAG enhances the cell survival signal against the accumulation of unfolded proteins, including polyQ, through not only proteasome activation, but also the activation of c-Fos-dependent AP-1.
AuthorsShun Nagashima, Toshifumi Fukuda, Yuka Kubota, Ayumu Sugiura, Mitsuyoshi Nakao, Ryoko Inatome, Shigeru Yanagi
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 39 Pg. 33879-89 (Sep 30 2011) ISSN: 1083-351X [Electronic] United States
PMID21832068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Peptides
  • Proto-Oncogene Proteins c-fos
  • Serum Response Factor
  • Transcription Factor AP-1
  • polyglutamine
  • Oxidoreductases Acting on Sulfur Group Donors
  • sulfiredoxin protein, mouse
  • Proteasome Endopeptidase Complex
  • CRAG protein, mouse
  • GTP Phosphohydrolases
Topics
  • Animals
  • Ataxia (metabolism, pathology)
  • Cell Line, Tumor
  • Cell Survival (genetics)
  • Enzyme Activation (genetics)
  • GTP Phosphohydrolases (genetics, metabolism)
  • Gene Expression Regulation (genetics)
  • Gene Knockdown Techniques
  • Mice
  • Mutation
  • Oxidoreductases Acting on Sulfur Group Donors (genetics, metabolism)
  • Peptides (genetics, metabolism)
  • Proteasome Endopeptidase Complex (genetics, metabolism)
  • Proto-Oncogene Proteins c-fos (genetics, metabolism)
  • Purkinje Cells (metabolism, pathology)
  • Serum Response Factor (genetics, metabolism)
  • Signal Transduction (genetics)
  • Transcription Factor AP-1 (genetics, metabolism)

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