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

Aab Cardiovascular Research Institute, University of Rochester, Rochester, New York 14642, USA.
The FASEB Journal (Impact Factor: 5.04). 12/2010; 24(12):4917-28. DOI: 10.1096/fj.10-162636
Source: PubMed


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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    • "Numerous studies have identified CSC-related genes, including transcription factors [31] [32], receptors [33] [34], and signaling factors [35] [36]. Thus, the abundance of one or some of these CSCrelated factors may be regulated by CHIP (quantity control), as CHIP regulates the quantity of its specific substrates by inducing protein degradation [2] [9] [10]. Alternatively, the accumulation of misfolded proteins due to CHIP depletion may cause for the changes in the expression of genes that function to maintain CSC properties, as CHIP regulates protein quality by inducing the degradation of misfolded proteins [5] [6] [7]. "
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    ABSTRACT: Cancer stem cells (CSCs) have several distinctive characteristics, including high metastatic potential, tumor-initiating potential, and properties that resemble normal stem cells such as self-renewal, differentiation, and drug efflux. Because of these characteristics, CSC is regarded to be responsible for cancer progression and patient prognosis. In our previous study, we showed that a ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein (CHIP) suppressed breast cancer malignancy. Moreover, a recent clinical study reported that CHIP expression levels were associated with favorable prognostic parameters of patients with breast cancer. Here we show that CHIP suppresses CSC properties in a population of breast cancer cells. CHIP depletion resulted in an increased proportion of CSCs among breast cancers when using several assays to assess CSC properties. From our results, we propose that inhibition of CSC properties may be one of the functions of CHIP as a suppressor of cancer progression.
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    • "Associations between CHIP and kinases such as ERK5 and Lim kinase 1 (LIMK1) have also been reported [54, 55]. The ERK5-CHIP interaction was shown to be an essential module operating downstream of IGF-1 induction having a cardioprotective effect mediated through inducible cAMP (cyclic adenosine monophosphate) early repressor (ICER) destabilization. "
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    ABSTRACT: The Carboxy-terminus of Hsc70 Interacting Protein (CHIP) is a co-chaperone E3 ligase containing three tandem repeats of tetratricopeptide (TPR) motifs and a C-terminal U-box domain separated by a central charged coiled-coil region. CHIP is known to function as a central quality-control E3 ligase and regulates several proteins involved in a myriad of physiological and pathological processes. Recent studies have highlighted varied regulatory mechanisms operating on the activity of CHIP which is crucial for cellular homeostasis. In this review article, we give a concise account of our current knowledge on the biochemistry and regulation of CHIP.
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    • "However the fact that CHIP has been demonstrated to be non-toxic in vitro, led us to question TH as a valid dopaminergic cell marker by which to determine neurodegeneration in the SNpc. The fact that CHIP is an E3-ubiquitin ligase with several know substrates [14], [15] raises the possibility of CHIP-mediated degradation of TH, which may appear as neuronal loss. In other words, viable dopaminergic neurons expressing CHIP would be wrongly excluded from our analysis when counting TH immunopositive cells because of CHIP-mediated TH degradation. "
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    ABSTRACT: Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity. Here we use a gene therapy approach to evaluate the applicability of the Hsp70 co-chaperone CHIP (C-terminal Hsp70 interacting protein) as a therapeutic candidate and examine its direct effect on alpha synuclein aggregates in vivo. Utilizing a novel viral vector mediated rat model to directly detect alpha synuclein aggregates, we show that CHIP can mediate the degradation of alpha synuclein aggregates in vivo. However, our studies also reveal that CHIP may potentially degrade tyrosine hydroxylase which would compromise the applicability of CHIP as a therapeutic approach for Parkinson's disease.
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