Article

Heat shock protein 90 regulates phosphatidylinositol 3-kinase-related protein kinase family proteins together with the RUVBL1/2 and Tel2-containing co-factor complex

Department of Molecular Biology, School of Medicine, Yokohama City University, Yokohama, Japan.
Cancer Science (Impact Factor: 3.52). 09/2011; 103(1):50-7. DOI: 10.1111/j.1349-7006.2011.02112.x
Source: PubMed

ABSTRACT

Heat shock protein 90 (Hsp90), a conserved molecular chaperone for a specific set of proteins critical for signal transduction including several oncogenic proteins, has been recognized as a promising target for anticancer therapy. Hsp90 inhibition also sensitizes cancer cells to DNA damage. However, the underlying mechanisms are not fully understood. Here, we provide evidence that Hsp90 is a general regulator of phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins, central regulators of stress responses including DNA damage. Inhibition of Hsp90 causes a reduction of all PIKK and suppresses PIKK-mediated signaling. In addition, Hsp90 forms complexes with RUVBL1/2 complex and Tel2 complex, both of which have been shown to interact with all PIKK and control their abundance and functions. These results suggest that Hsp90 can form multiple complexes with the RUVBL1/2 complex and Tel2 complex and function in the regulation of PIKK, providing additional rationale for the effectiveness of Hsp90 inhibition for anticancer therapy, including sensitization to DNA damage.

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Available from: Akio Yamashita, Jul 31, 2015
    • "The biological roles ascribed to the R2TP complex are directly associated with its ability to interact with the Hsp90 chaperone system and function as an Hsp90 cochaperone (Boulon et al., 2010; Izumi et al., 2012; Takai et al., 2010). In yeast, recruitment of R2TP to Hsp90 is mediated by Tah1, a TPR-domain protein that simultaneously binds the conserved C-terminal MEEVD motif of Hsp90 and a C-terminal region of Pih1 (Eckert et al., 2010). "
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    ABSTRACT: Client protein recruitment to the Hsp90 system depends on cochaperones that bind the client and Hsp90 simultaneously and facilitate their interaction. Hsp90 involvement in the assembly of snoRNPs, RNA polymerases, PI3-kinase-like kinases, and chromatin remodeling complexes depends on the TTT (Tel2-Tti1-Tti2), and R2TP complexes-consisting of the AAA-ATPases Rvb1 and Rvb2, Tah1 (Spagh/RPAP3 in metazoa), and Pih1 (Pih1D1 in humans)-that together provide the connection to Hsp90. The biochemistry underlying R2TP function is still poorly understood. Pih1 in particular, at the heart of the complex, has not been described at a structural level, nor have the multiple protein-protein interactions it mediates been characterized. Here we present a structural and biochemical analysis of Hsp90-Tah1-Pih1, Hsp90-Spagh, and Pih1D1-Tel2 complexes that reveal a domain in Pih1D1 specific for binding CK2 phosphorylation sites, and together define the structural basis by which the R2TP complex connects the Hsp90 chaperone system to the TTT complex.
    No preview · Article · Apr 2014 · Structure
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    • "The biological roles ascribed to the R2TP complex are directly associated with its ability to interact with the Hsp90 chaperone system and function as an Hsp90 cochaperone (Boulon et al., 2010; Izumi et al., 2012; Takai et al., 2010). In yeast, recruitment of R2TP to Hsp90 is mediated by Tah1, a TPR-domain protein that simultaneously binds the conserved C-terminal MEEVD motif of Hsp90 and a C-terminal region of Pih1 (Eckert et al., 2010). "
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    Full-text · Article · Jan 2014
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    • "PIKKs are central regulators of stress responses including DNA damage. Inhibition of Hsp90-RUVBL1/2 complex is effective for anticancer therapy [41]. "
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    ABSTRACT: Esophageal squamous cell cancer (ESCC) is one of the most common fatal human cancers. The identification of biomarkers for early detection could be a promising strategy to decrease mortality. Previous studies utilized microarray techniques to identify more than one hundred genes; however, it is desirable to identify a small set of biomarkers for clinical use. This study proposes a sequential forward feature selection algorithm to design decision tree models for discriminating ESCC from normal tissues. Two potential biomarkers of RUVBL1 and CNIH were identified and validated based on two public available microarray datasets. To test the discrimination ability of the two biomarkers, 17 pairs of expression profiles of ESCC and normal tissues from Taiwanese male patients were measured by using microarray techniques. The classification accuracies of the two biomarkers in all three datasets were higher than 90%. Interpretable decision tree models were constructed to analyze expression patterns of the two biomarkers. RUVBL1 was consistently overexpressed in all three datasets, although we found inconsistent CNIH expression possibly affected by the diverse major risk factors for ESCC across different areas.
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