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Science 25 May 2001:
Vol. 292. no. 5521, pp. 1552 - 1555
DOI: 10.1126/science.292.5521.1552
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Reports

Impairment of the Ubiquitin-Proteasome System by Protein Aggregation

Neil F. Bence, Roopal M. Sampat, Ron R. Kopito*

Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.

Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA.
*   To whom correspondence should be addressed. E-mail: kopito{at}stanford.edu

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Tau Aggregation and Toxicity in a Cell Culture Model of Tauopathy.
B. Bandyopadhyay, G. Li, H. Yin, and J. Kuret (2007)
J. Biol. Chem. 282, 16454-16464
   Abstract »    Full Text »    PDF »
The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta.
E. D. Watson, C. Geary-Joo, M. Hughes, and J. C. Cross (2007)
Development 134, 1809-1817
   Abstract »    Full Text »    PDF »
Perturbation of Endoplasmic Reticulum Homeostasis Facilitates Prion Replication.
C. Hetz, J. Castilla, and C. Soto (2007)
J. Biol. Chem. 282, 12725-12733
   Abstract »    Full Text »    PDF »
Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates.
H. Fukui and C. T. Moraes (2007)
Hum. Mol. Genet. 16, 783-797
   Abstract »    Full Text »    PDF »
Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure.
A. R. Shepard, N. Jacobson, J. C. Millar, I.-H. Pang, H. T. Steely, C. C. Searby, V. C. Sheffield, E. M. Stone, and A. F. Clark (2007)
Hum. Mol. Genet. 16, 609-617
   Abstract »    Full Text »    PDF »
High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways.
J. A. Yaglom, V. L. Gabai, and M. Y. Sherman (2007)
Cancer Res. 67, 2373-2381
   Abstract »    Full Text »    PDF »


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