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

Chang Hoon Woo, Nhat Tu Le, Tetsuro Shishido, Eugene Chang, Hakjoo Lee, Kyung Sun Heo, Deanne M. Mickelsen, Yan Lu, Carolyn McClain, Thomas Spangenberg, Chen Yan, Carlos Molina, Jay Yang, Cam Patterson, Jun Ichi Abe

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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.

Original languageEnglish
Pages (from-to)4917-4928
Number of pages12
JournalFASEB Journal
Volume24
Issue number12
DOIs
StatePublished - 1 Dec 2010

Fingerprint

HSC70 Heat-Shock Proteins
Ubiquitin-Protein Ligases
Ligases
Ubiquitin
Apoptosis
Degradation
Proteins
Small Interfering RNA
Assays
Intercellular Signaling Peptides and Proteins
Insulin
Ubiquitin C
Substrates
Runoff
Isoproterenol
Chemical activation
Cardiac Myocytes
Protein Binding
Muscle Cells
Transgenic Mice

Keywords

  • Cardiomyocyte apoptosis
  • Cell signaling
  • ICER
  • MAP kinase

Cite this

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 ; Yang, Jay ; Patterson, Cam ; Abe, Jun Ichi. / 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. In: FASEB Journal. 2010 ; Vol. 24, No. 12. pp. 4917-4928.
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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.",
keywords = "Cardiomyocyte apoptosis, Cell signaling, ICER, MAP kinase",
author = "Woo, {Chang Hoon} and Le, {Nhat Tu} and Tetsuro Shishido and Eugene Chang and Hakjoo Lee and Heo, {Kyung Sun} and Mickelsen, {Deanne M.} and Yan Lu and Carolyn McClain and Thomas Spangenberg and Chen Yan and Carlos Molina and Jay Yang and Cam Patterson and Abe, {Jun Ichi}",
year = "2010",
month = "12",
day = "1",
doi = "10.1096/fj.10-162636",
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Woo, CH, Le, NT, Shishido, T, Chang, E, Lee, H, Heo, KS, Mickelsen, DM, Lu, Y, McClain, C, Spangenberg, T, Yan, C, Molina, C, Yang, J, Patterson, C & Abe, JI 2010, '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', FASEB Journal, vol. 24, no. 12, pp. 4917-4928. https://doi.org/10.1096/fj.10-162636

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. / 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; Yang, Jay; Patterson, Cam; Abe, Jun Ichi.

In: FASEB Journal, Vol. 24, No. 12, 01.12.2010, p. 4917-4928.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Woo, Chang Hoon

AU - Le, Nhat Tu

AU - Shishido, Tetsuro

AU - Chang, Eugene

AU - Lee, Hakjoo

AU - Heo, Kyung Sun

AU - Mickelsen, Deanne M.

AU - Lu, Yan

AU - McClain, Carolyn

AU - Spangenberg, Thomas

AU - Yan, Chen

AU - Molina, Carlos

AU - Yang, Jay

AU - Patterson, Cam

AU - Abe, Jun Ichi

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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.

AB - 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.

KW - Cardiomyocyte apoptosis

KW - Cell signaling

KW - ICER

KW - MAP kinase

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DO - 10.1096/fj.10-162636

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