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Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor.

Growing evidence indicates a critical role of ubiquitin-proteosome system in apoptosis regulation. A cardioprotective effect of ubiquitin (Ub) ligase of the C terminus of Hsc70-interacting protein (CHIP) on myocytes has been reported. In the current study, we found that the cardioprotective effect of insulin growth factor-1 (IGF-1) was mediated by ERK5-CHIP signal module via inducible cAMP early repressor (ICER) destabilization. In vitro runoff assay and Ub assay showed ICER as a substrate of CHIP Ub ligase. Both disruption of ERK5-CHIP binding with inhibitory helical linker domain fragment (aa 101-200) of CHIP and the depletion of ERK5 by siRNA inhibited CHIP Ub ligase activity, which suggests an obligatory role of ERK5 on CHIP activation. Depletion of CHIP, using siRNA, inhibited IGF-1-mediated reduction of isoproterenol-mediated ICER induction and apoptosis. In diabetic mice subjected to myocardial infarction, the CHIP Ub ligase activity was decreased, with an increase in ICER expression. These changes were attenuated significantly in a cardiac-specific constitutively active form of MEK5α transgenic mice (CA-MEK5α-Tg) previously shown to have greater functional recovery. Furthermore, pressure overload-mediated ICER induction was enhanced in heterozygous CHIP(+/-) mice. We identified ICER as a novel CHIP substrate and that the ERK5-CHIP complex plays an obligatory role in inhibition of ICER expression, cardiomyocyte apoptosis, and cardiac dysfunction.

Pubmed ID: 20724525


  • Woo CH
  • Le NT
  • Shishido T
  • Chang E
  • Lee H
  • Heo KS
  • Mickelsen DM
  • Lu Y
  • McClain C
  • Spangenberg T
  • Yan C
  • Molina CA
  • Yang J
  • Patterson C
  • Abe J


FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Data

December 2, 2010

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL-077789
  • Agency: NHLBI NIH HHS, Id: HL-88637
  • Agency: NIGMS NIH HHS, Id: R01 GM061728
  • Agency: NHLBI NIH HHS, Id: R01 HL064839
  • Agency: NHLBI NIH HHS, Id: R01 HL088400
  • Agency: NHLBI NIH HHS, Id: R01 HL088637
  • Agency: NHLBI NIH HHS, Id: R01 HL102746
  • Agency: NHLBI NIH HHS, Id: R01 HL108551
  • Agency: NHLBI NIH HHS, Id: R37 HL065619

Mesh Terms

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Blotting, Western
  • Cells, Cultured
  • Cyclic AMP
  • Cyclic AMP Response Element Modulator
  • Echocardiography
  • Immunoprecipitation
  • Mitogen-Activated Protein Kinase 7
  • Myocytes, Cardiac
  • Protein Binding
  • Protein Stability
  • RNA, Small Interfering
  • Rats
  • Rats, Sprague-Dawley
  • Ubiquitin-Protein Ligases