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Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110.

ABSTRACT: A network of heat-shock proteins mediates cellular protein homeostasis, and has a fundamental role in preventing aggregation-associated neurodegenerative diseases. In a Drosophila model of polyglutamine (polyQ) disease, the HSP40 family protein, DNAJ-1, is a superior suppressor of toxicity caused by the aggregation of polyQ containing proteins. Here, we demonstrate that one specific HSP110 protein, 70 kDa heat-shock cognate protein cb (HSC70cb), interacts physically and genetically with DNAJ-1 in vivo, and that HSC70cb is necessary for DNAJ-1 to suppress polyglutamine-induced cell death in Drosophila. Expression of HSC70cb together with DNAJ-1 significantly enhanced the suppressive effects of DNAJ-1 on polyQ-induced neurodegeneration, whereas expression of HSC70cb alone did not suppress neurodegeneration in Drosophila models of either general polyQ disease or Huntington's disease. Furthermore, expression of a human HSP40, DNAJB1, together with a human HSP110, APG-1, protected cells from polyQ-induced neural degeneration in flies, whereas expression of either component alone had little effect. Our data provide a functional link between HSP40 and HSP110 in suppressing the cytotoxicity of aggregation-prone proteins, and suggest that HSP40 and HSP110 function together in protein homeostasis control.

SUBMITTER: Kuo Y

PROVIDER: S-EPMC3824661 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110.

Kuo Y Y Ren S S Lao U U Edgar B A BA Wang T T

Cell death & disease 20131003

A network of heat-shock proteins mediates cellular protein homeostasis, and has a fundamental role in preventing aggregation-associated neurodegenerative diseases. In a Drosophila model of polyglutamine (polyQ) disease, the HSP40 family protein, DNAJ-1, is a superior suppressor of toxicity caused by the aggregation of polyQ containing proteins. Here, we demonstrate that one specific HSP110 protein, 70 kDa heat-shock cognate protein cb (HSC70cb), interacts physically and genetically with DNAJ-1 i ...[more]

PMID: 24091676

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Project description:Heat shock proteins (HSPs) are evolutionarily conserved chaperones occurring in virtually all living organisms playing a key role in the maintenance of cellular homeostasis. They are constitutively expressed to prevent and repair protein damage following various physiological and environmental stressors. HSPs are overexpressed in various types of cancers to provide cytoprotective function, and they have been described to influence prognosis and response to therapy. Moreover, they have been used as a tumor marker in blood serum biochemistry and they represent a potentially promising therapeutic target. To clarify prognostic significance of two canonical HSPs (27 and 70) and less known HSP110 (previously known as HSP105) in colorectal carcinoma (CRC), we retrospectively performed HSP immunohistochemistry on tissue microarrays from formalin-fixed paraffin-embedded tumor tissue from 297 patients with known follow-up. Survival analysis (univariate Kaplan-Meier analysis with the log-rank test and multivariate Cox regression) revealed significantly shorter overall survival (OS, mean 5.54 vs. 7.07, p = 0.033) and borderline insignificantly shorter cancer specific survival (CSS, mean 6.3 vs. 7.87 years, p = 0.066) in patients with HSP70+ tumors. In the case of HSP27+ tumors, there was an insignificantly shorter OS (mean 6.36 vs. 7.13 years, p = 0.2) and CSS (mean 7.17 vs. 7.95 years, p = 0.2). HSP110 showed no significant impact on survival. Using Pearson's chi-squared test, there was a significant association of HSP27 and HSP70 expression with advanced cancer stage. HSP27+ tumors were more frequently mismatch-repair proficient and vice versa (p = 0.014), and they occurred more often in female patients and vice versa (p = 0.015). There was an enrichment of left sided tumors with HSP110+ compared to the right sided (p = 0.022). In multivariate Cox regression adjusted on the UICC stage, grade and right/left side; both HSPs 27 and 70 were not independent survival predictors (p = 0.616 & p = 0.586). In multivariate analysis, only advanced UICC stage (p = 0) and right sided localization (p = 0.04) were independent predictors of worse CSS. In conclusion, from all three HSPs examined in our study, only HSP70 expression worsened CRC prognosis, although stage-dependent. The contribution of this article may be seen as a large survival analysis of HSPs 27 and 70 and the largest analysis of HSP110 described in CRC.

Project description:Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is of serious clinical concern. Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is beneficial as a drug for treating non-small cell lung cancer; however, this drug induces ILD and the molecular mechanisms underpinning this condition remain unclear. We recently reported that expression of heat shock protein 70 (HSP70) protects against bleomycin-induced pulmonary fibrosis, an animal model of pulmonary fibrosis. In this study, we have examined the effects of drugs known to induce ILD clinically on the expression of HSP70 in cultured lung epithelial cells and have found that gefitinib has a suppressive effect. Results of a luciferase reporter assay, pulse-labelling analysis of protein and experiments using an inhibitor of translation or transcription suggest that gefitinib suppresses the expression of HSP70 at the level of translation. Furthermore, the results of experiments with siRNA for Dicer1, an enzyme responsible for synthesis of microRNA, and real-time RT-PCR analysis suggest that some microRNAs are involved in the gefitinib-induced translational inhibition of HSP70. Mutations in the EGFR affect the concentration of gefitinib required for suppressing the expression of HSP70. These results suggest that gefitinib suppresses the translation of HSP70 through an EGFR- and microRNA-mediated mechanism. In vivo, while oral administration of gefitinib suppressed the pulmonary expression of HSP70 and exacerbated bleomycin-induced pulmonary fibrosis in wild-type mice, these effects were not as distinct in transgenic mice expressing HSP70. Furthermore, oral co-administration of geranylgeranylacetone (GGA), an inducer of HSP70, suppressed gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis. Taken together, these findings suggest that gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis is mediated by suppression of pulmonary expression of HSP70 and that an inducer of HSP70 expression, such as GGA, may be therapeutically beneficial for the treatment of gefitinib-induced pulmonary fibrosis.

Dataset Information

Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110.

Publications

Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110.

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