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Enhancement of proteasome‐linked TonEBP/NFAT5 degradation in cardiomyocytes exposed to doxorubicin
Author(s) -
Ito Takashy,
Fujio Yasushi,
Azuma Junichi
Publication year - 2008
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.22.1_supplement.589.3
Subject(s) - downregulation and upregulation , proteasome , osmolyte , proteolysis , chemistry , doxorubicin , microbiology and biotechnology , stimulation , osmotic shock , small interfering rna , cardiotoxicity , proteasome inhibitor , endocrinology , biochemistry , biology , rna , medicine , toxicity , enzyme , gene , organic chemistry , chemotherapy
TonEBP is a transcriptional factor that regulates the induction of transporters and enzymes involved in organic osmolyte accumulation by hypertonic stimulation. Although TonEBP is ubiquitously expressed and plays an important role during osmotic stress, little is known about its role and regulation in pathological states that are associated with no osmotic imbalance. To determine whether TonEBP might respond to pathological stimuli in the absence of osmotic stress, levels of the taurine transporter (TauT), a target of TonEBP, were examined in cardiomyocytes exposed for 24 h to the cardiotoxic agent, doxorubicin (Dox). The Dox treated cells exhibited reduced TauT and nuclear TonEBP protein content. Since the decline in TonEBP protein content was prevented by proteasome inhibitors but was not associated with a change in TonEBP mRNA content, Dox appears to accelerate the degradation of TonEBP. This decrease in TonEBP content may have significant consequences, as downregulation of TonEBP using either siRNA or overexpression of dominant‐negative TonEBP leads to reduced myocyte viability. In conclusion, Dox mediates the degradation of TonEBP via a proteasome‐related proteolysis pathway, a reaction that plays is an important role in Dox‐induced cardiotoxicity.