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Doxorubicin Activates Ubiquitin‐Proteasome System Mediated Proteolysis by Acting on Both Ubiquitination Apparatuses and the Proteasome
Author(s) -
Liu Jinbao,
Zheng Hanqiao,
Tang Mingxin,
Wang Xuejun
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1024
Subject(s) - proteasome , ubiquitin , ubiquitin ligase , microbiology and biotechnology , activator (genetics) , doxorubicin , proteolysis , chemistry , protein degradation , biology , biochemistry , enzyme , gene , genetics , chemotherapy
The ubiquitin proteasome system (UPS) degrades all abnormal proteins and most normal proteins that are no longer needed, thereby playing critical roles in protein quality control and homeostasis in the cell. Proteasome inhibition has proven to be effective in treating certain forms of cancer while UPS impairment is increasingly implicated in the pathogenesis of many severe and yet common diseases. To establish the pathogenic role of UPS malfunction a UPS activator is required. We previously reported that doxorubicin (Dox) enhances the degradation of a UPS reporter in mouse hearts. To address the underlying mechanism, here we report that: Dox not only enhances the degradation of an exogenous UPS reporter (GFPu) but also antagonizes proteasome inhibitor induced accumulation of endogenous substrates (e.g., β‐catenin, c‐Jun) of the UPS in cultured NIH3T3 cells and cardiomyocytes; Dox facilitates in vitro degradation of GFPu and c‐Jun by either 3T3 cell lysates or the purified UPS; Dox directly stimulates the peptidase activities of purified 20S proteasomes at a low dose (1μM) but inhibits them at a higher dose (10μM); Dox attenuates MG‐132‐induced accumulation of neddylated cullin1; and Dox stabilizes E3 ligase CHIP while proteasome inhibition depletes CHIP in 3T3 cells. These new findings suggest that Dox activates the UPS by acting directly on both ubiquitination apparatuses and the proteasome.