RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Woo, Chang-Hoon  Le, Nhat-Tu  Shishido, Tetsuro  Chang, Eugene  Lee, Hakjoo  Heo, Kyung-Sun  Mickelsen, Deanne M  Lu, Yan  McClain, Carolyn  Spangenberg, Thomas  Yan, Chen  Molina, Carlos A  Yang, Jay  Patterson, Cam  Abe, Jun-ichi 
Citation: Woo CH, etal., FASEB J. 2010 Dec;24(12):4917-28. doi: 10.1096/fj.10-162636. Epub 2010 Aug 19.
RGD ID: 401901210
Pubmed: PMID:20724525   (View Abstract at PubMed)
PMCID: PMC2992371   (View Article at PubMed Central)
DOI: DOI:10.1096/fj.10-162636   (Journal Full-text)

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.




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Molecular Function

  
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Original Reference(s)
Stub1Ratubiquitin protein ligase activity enablesIDA PMID:20724525UniProt 


Genes (Rattus norvegicus)
Igf1  (insulin-like growth factor 1) Map2k5  (mitogen activated protein kinase kinase 5) Mapk7  (mitogen-activated protein kinase 7)
Stub1  (STIP1 homology and U-box containing protein 1)