A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome

Jinbao Liu, Hanqiao Zheng, Mingxin Tang, Youn Chul Ryu, Xuejun Wang

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56 Citations (Scopus)

Abstract

The ubiquitin proteasome system (UPS) degrades abnormal proteins and most unneeded normal proteins, thereby playing a critical role in protein homeostasis in the cell. Proteasome inhibition is effective in treating certain forms of cancer, while UPS dysfunction is increasingly implicated in the pathogenesis of many severe and yet common diseases. It has been previously shown that doxorubicin (Dox) enhances the degradation of a UPS surrogate substrate in mouse hearts. To address the underlying mechanism, in the present study, we report that 1) Dox not only enhances the degradation of an exogenous UPS reporter (GFPu) but also antagonizes the proteasome inhibitor-induced accumulation of endogenous substrates (e.g., β-catenin and c-Jun) of the UPS in cultured NIH 3T3 cells and cardiomyocytes; 2) Dox facilitates the in vitro degradation of GFPu and c-Jun by the reconstituted UPS via the enhancement of proteasomal function; 3) Dox at a therapeutically relevant dose directly stimulates the peptidase activities of purified 20S proteasomes; and 4) Dox increases, whereas proteasome inhibition decreases, E3 ligase COOH-terminus of heat shock protein cognate 70 in 3T3 cells via a posttranscriptional mechanism. These new findings suggest that Dox activates the UPS by acting directly on both the ubiquitination apparatus and proteasome.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number6
DOIs
StatePublished - Dec 1 2008

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Ubiquitination
Proteasome Endopeptidase Complex
Ubiquitin
Doxorubicin
Proteolysis
Therapeutics
HSC70 Heat-Shock Proteins
Catenins
3T3 Cells
NIH 3T3 Cells
Proteins
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Cardiac Myocytes
Homeostasis
Peptide Hydrolases

Keywords

  • COOH-terminus of heat shock protein cognate 70-interacting protein
  • Cardiomyocytes
  • Heat shock protein 70

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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title = "A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome",
abstract = "The ubiquitin proteasome system (UPS) degrades abnormal proteins and most unneeded normal proteins, thereby playing a critical role in protein homeostasis in the cell. Proteasome inhibition is effective in treating certain forms of cancer, while UPS dysfunction is increasingly implicated in the pathogenesis of many severe and yet common diseases. It has been previously shown that doxorubicin (Dox) enhances the degradation of a UPS surrogate substrate in mouse hearts. To address the underlying mechanism, in the present study, we report that 1) Dox not only enhances the degradation of an exogenous UPS reporter (GFPu) but also antagonizes the proteasome inhibitor-induced accumulation of endogenous substrates (e.g., β-catenin and c-Jun) of the UPS in cultured NIH 3T3 cells and cardiomyocytes; 2) Dox facilitates the in vitro degradation of GFPu and c-Jun by the reconstituted UPS via the enhancement of proteasomal function; 3) Dox at a therapeutically relevant dose directly stimulates the peptidase activities of purified 20S proteasomes; and 4) Dox increases, whereas proteasome inhibition decreases, E3 ligase COOH-terminus of heat shock protein cognate 70 in 3T3 cells via a posttranscriptional mechanism. These new findings suggest that Dox activates the UPS by acting directly on both the ubiquitination apparatus and proteasome.",
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AU - Zheng, Hanqiao

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AU - Ryu, Youn Chul

AU - Wang, Xuejun

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