Rapid degradation of bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons

Robert Meller, Jennifer Anastasia Cameron, Daniel John Torrey, Corrin Erin Clayton, Andrea Nicole Ordonez, David Clifford Henshall, Manabu Minami, Clara Kay Schindler, Julie Saugstad, Roger Pancoast Simon

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

A previous exposure to a non-harmful ischemic insult (preconditioning) protects the brain against subsequent harmful ischemia (ischemic tolerance). In contrast to delayed gene-mediated ischemic tolerance, little is known about the molecular mechanisms that regulate rapid ischemic tolerance, which occurs within 1 h following preconditioning. Here we have investigated the degradation of the pro-apoptotic Bcl-2 family member Bim as a mechanism of rapid ischemic tolerance. Bim protein levels were reduced 1 h following preconditioning and occurred concurrent with an increase in Bim ubiquitination. Ubiquitinated proteins are degraded by the proteasome, and inhibition of the proteasome with MG132 (a proteasome inhibitor) prevented Bim degradation and blocked rapid ischemic tolerance. Inhibition of p42/p44 mitogen-activated protein kinase activation by U0126 reduced Bim ubiquitination and Bim degradation and blocked rapid ischemic tolerance. Finally, inhibition of Bim expression using antisense oligonucleotides also reduced cell death following ischemic challenge. Our results suggest that following preconditioning ischemia, Bim is rapidly degraded by the ubiquitin-proteasome system, resulting in rapid ischemic tolerance. This suggests that the rapid degradation of cell death-promoting proteins by the ubiquitin-proteasome pathway may represent a novel therapeutic strategy to reduce cell damage following neuropathological insults, e.g. stroke.

Original languageEnglish (US)
Pages (from-to)7429-7436
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number11
DOIs
StatePublished - Mar 17 2006
Externally publishedYes

Fingerprint

Proteasome Endopeptidase Complex
Ubiquitin
Neurons
Degradation
Ischemic Preconditioning
Ubiquitination
Cell Death
Ubiquitinated Proteins
Proteasome Inhibitors
Antisense Oligonucleotides
Mitogen-Activated Protein Kinase 1
Cell death
Proteins
Stroke
Brain
Mitogen-Activated Protein Kinases
Genes
Inhibition (Psychology)
Chemical activation
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Meller, R., Cameron, J. A., Torrey, D. J., Clayton, C. E., Ordonez, A. N., Henshall, D. C., ... Simon, R. P. (2006). Rapid degradation of bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. Journal of Biological Chemistry, 281(11), 7429-7436. https://doi.org/10.1074/jbc.M512138200

Rapid degradation of bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. / Meller, Robert; Cameron, Jennifer Anastasia; Torrey, Daniel John; Clayton, Corrin Erin; Ordonez, Andrea Nicole; Henshall, David Clifford; Minami, Manabu; Schindler, Clara Kay; Saugstad, Julie; Simon, Roger Pancoast.

In: Journal of Biological Chemistry, Vol. 281, No. 11, 17.03.2006, p. 7429-7436.

Research output: Contribution to journalArticle

Meller, R, Cameron, JA, Torrey, DJ, Clayton, CE, Ordonez, AN, Henshall, DC, Minami, M, Schindler, CK, Saugstad, J & Simon, RP 2006, 'Rapid degradation of bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons', Journal of Biological Chemistry, vol. 281, no. 11, pp. 7429-7436. https://doi.org/10.1074/jbc.M512138200
Meller, Robert ; Cameron, Jennifer Anastasia ; Torrey, Daniel John ; Clayton, Corrin Erin ; Ordonez, Andrea Nicole ; Henshall, David Clifford ; Minami, Manabu ; Schindler, Clara Kay ; Saugstad, Julie ; Simon, Roger Pancoast. / Rapid degradation of bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 11. pp. 7429-7436.
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