title: 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.
abstract: 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.
authors: Aab Cardiovascular Research Institute, University of Rochester, Rochester, New York 14642, USA.
authors: Chang-Hoon
authors: CH
authors: Woo
authors: Nhat-Tu
authors: NT
authors: Le
authors: Tetsuro
authors: T
authors: Shishido
authors: Eugene
authors: E
authors: Chang
authors: Hakjoo
authors: H
authors: Lee
authors: Kyung-Sun
authors: KS
authors: Heo
authors: Deanne M
authors: DM
authors: Mickelsen
authors: Yan
authors: Y
authors: Lu
authors: Carolyn
authors: C
authors: McClain
authors: Thomas
authors: T
authors: Spangenberg
authors: Chen
authors: C
authors: Yan
authors: Carlos A
authors: CA
authors: Molina
authors: Jay
authors: J
authors: Yang
authors: Cam
authors: C
authors: Patterson
authors: Jun-ichi
authors: J
authors: Abe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D004452:Echocardiography; D047468:Immunoprecipitation; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C497412:Crem protein, rat; D034741:RNA, Small Interfering; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; C540442:Stub1 protein, rat; D044767:Ubiquitin-Protein Ligases; D048054:Mitogen-Activated Protein Kinase 7