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
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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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    • "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.
    The Scientific World Journal 12/2013; 2013:782031. DOI:10.1155/2013/782031 · 1.73 Impact Factor
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    • ", TEL2 [20], phosphorylated TEL2 (P-TEL2) [18], CK2α (Santa Cruz Biotechnology ) and β-actin (Santa Cruz Biotechnology). Antibodies were diluted 1:200–1:5000 in 5% non-fat dry milk, 0.1% Tween 20/TBS and incubated overnight at 4 °C with rocking. "
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    ABSTRACT: Nonsense-mediated mRNA decay (NMD) is the best-characterized mRNA surveillance mechanism that degrades a premature-termination codon (PTC)-containing mRNA. During mammalian NMD, SMG1 and UPF1, key proteins in NMD, join at a PTC and form an SMG1-UPF1-eRF1-eRF3 (SURF) complex by binding UPF1 to eRF3 after PTC-recognition by the translating ribosome. Subsequently, UPF1 is phosphorylated after UPF1-SMG1 moves onto the downstream exon junction complex (EJC). However, the cellular events that induce UPF1 and SMG1 complex formation and increase NMD efficiency before PTC recognition remain unclear. Here, we show that telomere-maintenance 2 (TEL2) phosphorylation by casein-kinase 2 (CK2) increases SMG1 stability, which increases UPF1 phosphorylation and, ultimately, augments NMD. Inhibition of CK2 activity or downregulation of TEL2 impairs NMD. Intriguingly, loss of TEL2 phosphorylation reduces UPF1-bound PTC-containing mRNA and the formation of the SMG1-UPF1 complex. Thus, our results identify a new function of CK2-mediated TEL2 phosphorylation in a mammalian NMD.
    Biochimica et Biophysica Acta 07/2013; 1829(10). DOI:10.1016/j.bbagrm.2013.06.002 · 4.66 Impact Factor
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