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Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent
Tomohisa Horibe, Masayuki Kohno, Mari Haramoto, Koji Ohara, Koji Kawakami
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-8
Abstract: We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.Heat-shock protein 90 (Hsp90) is a molecular chaperone [1] that participates in the quality control of protein folding. The mechanism of action of Hsp90 includes sequential ATPase cycles and the stepwise recruitment of cochaperones, including Hsp70, CDC37, p60/Hsp-organizing protein (Hop), and p23 [2,3]. In particular, Hsp90 and Hsp70 interact with numerous cofactors containing so-called tetratricopeptide repeat (TPR) domains. TPR domains are composed of loosely conserved 34-amino acid sequence motifs that are repeated between one and 16 times per domain. Originally identified in components of the anaphase-promoting complex [4,5], TPR domains are now known to mediate specific protein interactions in numerous cellular contexts [6-8]. Moreover, apart from serving mere anchoring functions, TPR domains of the chaperone cofactors Hip and p60/Hop also are able to regulate the ATPase activities of Hsp70 and Hsp90, respectively [9,10]. Each 34-amino acid motif forms a pair of antiparallel α-helices. These motifs are arranged in a tandem array into a superhelical structure that encloses a central groove. The TPR-domain-containing cofactors of the Hsp70/Hsp
The Human TPR Protein TTC4 Is a Putative Hsp90 Co-Chaperone Which Interacts with CDC6 and Shows Alterations in Transformed Cells  [PDF]
Gilles Crevel, Dorothy Bennett, Sue Cotterill
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001737
Abstract: Background The human TTC4 protein is a TPR (tetratricopeptide repeat) motif-containing protein. The gene was originally identified as being localized in a genomic region linked to breast cancer and subsequent studies on melanoma cell lines revealed point mutations in the TTC4 protein that may be associated with the progression of malignant melanoma. Methodology/Principle Findings Here we show that TTC4 is a nucleoplasmic protein which interacts with HSP90 and HSP70, and also with the replication protein CDC6. It has significant structural and functional similarities with a previously characterised Drosophila protein Dpit47. We show that TTC4 protein levels are raised in malignant melanoma cell lines compared to melanocytes. We also see increased TTC4 expression in a variety of tumour lines derived from other tissues. In addition we show that TTC4 proteins bearing some of the mutations previously identified from patient samples lose their interaction with the CDC6 protein. Conclusions/Significance Based on these results and our previous work with the Drosophila Dpit47 protein we suggest that TTC4 is an HSP90 co-chaperone protein which forms a link between HSP90 chaperone activity and DNA replication. We further suggest that the loss of the interaction with CDC6 or with additional client proteins could provide one route through which TTC4 could influence malignant development of cells.
Cytotoxicity of catechol towards human glioblastoma cells via superoxide and reactive quinones generation
Pereira, Marco Roberto Guimar?es;Oliveira, Elineusa Silva de;Villar, Flávio Augusto Guerreiro Arag?o de;Grangeiro, Maria Socorro;Fonseca, Júlia;Silva, Ana Rita;Costa, Maria de Fátima Dias;Costa, Sílvia Lima;El-Bachá, Ramon dos Santos;
Jornal Brasileiro de Patologia e Medicina Laboratorial , 2004, DOI: 10.1590/S1676-24442004000400012
Abstract: it is known that the exposure to benzene in the petroleum industry causes lympho-haematopoietic cancer among workers. however, there is little data concerning the toxicity of benzene to the central nervous system. benzene easily penetrates the brain where it is metabolized to catechol. since catechol autoxidizes in physiological phosphate buffer, we hypothesized that it could be toxic towards glial cells due to the generation of reactive oxygen species and quinones. in this work we studied the cytotoxic properties of catechol towards human glioblastoma cells. we found that catechol was toxic towards these cells after 72 hours and this toxicity was related to the formation of quinones. catechol at 230μm killed 50% of cells. the catechol-induced cytotoxicity was prevented by the addition of 100u superoxide dismutase, which also inhibited the formation of quinones. these data suggest that catechol induces cytotoxicity via the extracellular generation of superoxide and quinones.
A Novel Extracellular Hsp90 Mediated Co-Receptor Function for LRP1 Regulates EphA2 Dependent Glioblastoma Cell Invasion  [PDF]
Udhayakumar Gopal,Jessica E. Bohonowych,Carla Lema-Tome,Angen Liu,Elizabeth Garrett-Mayer,Bingcheng Wang,Jennifer S. Isaacs
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017649
Abstract: Extracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2S897). We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling.
Inhibition of NF-κB by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and γ-Radiation Cytotoxicity in Glioblastoma Cells  [PDF]
M. S. Brassesco,G. M. Roberto,A. G. Morales,J. C. Oliveira,L. E. A. Delsin,J. A. Pezuk,E. T. Valera,C. G. Carlotti Jr.,E. M. Rego,H. F. de Oliveira,C. A. Scrideli,K. Umezawa,L. G. Tone
Chemotherapy Research and Practice , 2013, DOI: 10.1155/2013/593020
Abstract: Despite advances in neurosurgery and aggressive treatment with temozolomide (TMZ) and radiation, the overall survival of patients with glioblastoma (GBM) remains poor. Vast evidence has indicated that the nuclear factor NF-κB is constitutively activated in cancer cells, playing key roles in growth and survival. Recently, Dehydroxymethylepoxyquinomicin (DHMEQ) has shown to be a selective NF-κB inhibitor with antiproliferative properties in GBM. In the present study, the ability of DHMEQ to surmount tumor's invasive nature and therapy resistance were further explored. Corroborating results showed that DHMEQ impaired cell growth in dose- and time-dependent manners with G2/M arrest when compared with control. Clonogenicity was also significantly diminished with increased apoptosis, though necrotic cell death was also observed at comparable levels. Notably, migration and invasion were inhibited accordingly with lowered expression of invasion-related genes. Moreover, concurrent combination with TMZ synergistically inhibited cell growth in all cell lines, as determined by proliferation and caspase-3 activation assays, though in those that express O6-methylguanine-DNA methyltransferase, the synergistic effects were schedule dependent. Pretreatment with DHMEQ equally sensitized cells to ionizing radiation. Taken together, our results strengthen the potential usefulness of DHMEQ in future therapeutic strategies for tumors that do not respond to conventional approaches. 1. Introduction Glioblastoma (GBM) is the most aggressive primary brain tumor [1]. Despite improvements in neurosurgery, radiation management, and the advent of temozolomide (TMZ), the outcome of patients remains extremely poor, with a mean life expectancy of approximately one year [2], owing to its ability to infiltrate/invade surrounding tissues and inherent radio- and chemoresistance. Over the past decade, compelling evidence demonstrated that constitutive activation of NF-κB and aberrant regulation of the signaling pathways that control its activity are involved in cancer development and progression, as well as in resistance to therapy in many types of malignancies including GBM [3–6]. Thus, inhibition of the NF-κB pathway seems to be a promising option to improve the efficacy of conventional anticancer therapies. A plethora of NF-κB inhibitors has shown to be effective against various carcinomas and lymphomas (including proteasome inhibitors, IKK inhibitors, and inhibitors of IkB phosphorylation) [7], though, most of them barely discriminate between malignant and normal cells and result in
Protein evolution of ANTP and PRD homeobox genes
Nuno A Fonseca, Cristina P Vieira, Peter WH Holland, Jorge Vieira
BMC Evolutionary Biology , 2008, DOI: 10.1186/1471-2148-8-200
Abstract: In this study, we report a method for the fast and efficient retrieval of sequences belonging to the ANTP (HOXL and NKL) and PRD classes. Furthermore, we look for diagnostic amino acid residues that can be used to distinguish HOXL, NKL and PRD genes.The reported protein features will facilitate the robust classification of homeobox genes from newly sequenced bilaterian genomes. Nevertheless, in non-bilaterian genomes our findings must be cautiously applied. In principle, as long as a good manually curated data set is available the approach here described can be applied to non-bilaterian organisms as well. Our results help focus experimental studies onto investigating the biochemical functions of key homeodomain residues in different gene classes.Genes that belong to the homeobox family are characterized by the ability to code for a protein that contains a recognizable, although very variable, 'homeodomain', usually 60 amino acids in length [1,2]. Many of these genes are transcription factors that play important roles in the embryonic development of bilaterian and non-bilaterian animals. Changes in homeobox gene content and deployment during evolution may have contributed to the evolution of body plan differences in animals [3-5]. Therefore, comparison of homeobox gene sets from different animals may shed light on the evolutionary events that gave rise to animal body plan diversity. Nevertheless, gene orthology is not always easy to establish when comparing divergent animals [6]. For this purpose, phylogenetic analysis, conservation of synteny, paralogy within the human genome, insertions within the homeodomain, key amino acid residues, and several motifs outside of the homeodomain can all be used. These features can also be used to classify homeobox genes into classes, subclasses and families. In the latest revision, Holland et al. [6] classified all 235 human homeobox genes into 11 classes (ANTP, PRD, LIM, POU, HNF, SINE, TALE, CUT, PROS, ZF and CERS) and 102 gene
Ligand Recognition by the TPR Domain of the Import Factor Toc64 from Arabidopsis thaliana  [PDF]
Rashmi Panigrahi, Abdussalam Adina-Zada, James Whelan, Alice Vrielink
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083461
Abstract: The specific targeting of protein to organelles is achieved by targeting signals being recognised by their cognate receptors. Cytosolic chaperones, bound to precursor proteins, are recognized by specific receptors of the import machinery enabling transport into the specific organelle. The aim of this study was to gain greater insight into the mode of recognition of the C-termini of Hsp70 and Hsp90 chaperones by the Tetratricopeptide Repeat (TPR) domain of the chloroplast import receptor Toc64 from Arabidopsis thaliana (At). The monomeric TPR domain binds with 1:1 stoichiometry in similar micromolar affinity to both Hsp70 and Hsp90 as determined by isothermal titration calorimetry (ITC). Mutations of the terminal EEVD motif caused a profound decrease in affinity. Additionally, this study considered the contributions of residues upstream as alanine scanning experiments of these residues showed reduced binding affinity. Molecular dynamics simulations of the TPR domain helices upon peptide binding predicted that two helices within the TPR domain move backwards, exposing the cradle surface for interaction with the peptide. Our findings from ITC and molecular dynamics studies suggest that AtToc64_TPR does not discriminate between C-termini peptides of Hsp70 and Hsp90.
The Early ANTP Gene Repertoire: Insights from the Placozoan Genome  [PDF]
Bernd Schierwater, Kai Kamm, Mansi Srivastava, Daniel Rokhsar, Rafael D. Rosengarten, Stephen L. Dellaporta
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002457
Abstract: The evolution of ANTP genes in the Metazoa has been the subject of conflicting hypotheses derived from full or partial gene sequences and genomic organization in higher animals. Whole genome sequences have recently filled in some crucial gaps for the basal metazoan phyla Cnidaria and Porifera. Here we analyze the complete genome of Trichoplax adhaerens, representing the basal metazoan phylum Placozoa, for its set of ANTP class genes. The Trichoplax genome encodes representatives of Hox/ParaHox-like, NKL, and extended Hox genes. This repertoire possibly mirrors the condition of a hypothetical cnidarian-bilaterian ancestor. The evolution of the cnidarian and bilaterian ANTP gene repertoires can be deduced by a limited number of cis-duplications of NKL and “extended Hox” genes and the presence of a single ancestral “ProtoHox” gene.
TPR鞋用材料  [PDF]
郑玉婴
福州大学学报(自然科学版) , 2001,
Abstract: 分析了TPR鞋用材料的配方、工艺、性能 .实验结果表明 ,该材料具有高弹性、耐低温、粘结强度牢等特点 ,适用于生产中高档运动鞋和旅游鞋鞋底 .
In Silico Identification of Carboxylate Clamp Type Tetratricopeptide Repeat Proteins in Arabidopsis and Rice As Putative Co-Chaperones of Hsp90/Hsp70  [PDF]
Bishun D. Prasad,Shilpi Goel,Priti Krishna
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012761
Abstract: The essential eukaryotic molecular chaperone Hsp90 operates with the help of different co-chaperones, which regulate its ATPase activity and serve as adaptors to recruit client proteins and other molecular chaperones, such as Hsp70, to the Hsp90 complex. Several Hsp90 and Hsp70 co-chaperones contain the tetratricopeptide repeat (TPR) domain, which interacts with the highly conserved EEVD motif at the C-terminal ends of Hsp90 and Hsp70. The acidic side chains in EEVD interact with a subset of basic residues in the TPR binding pocket called a ‘carboxylate clamp’. Since the carboxylate clamp residues are conserved in the TPR domains of known Hsp90/Hsp70 co-chaperones, we carried out an in silico search for TPR proteins in Arabidopsis and rice comprising of at least one three-motif TPR domain with conserved amino acid residues required for Hsp90/Hsp70 binding. This approach identified in Arabidopsis a total of 36 carboxylate clamp (CC)-TPR proteins, including 24 novel proteins, with potential to interact with Hsp90/Hsp70. The newly identified CC-TPR proteins in Arabidopsis and rice contain additional protein domains such as ankyrin, SET, octicosapeptide/Phox/Bem1p (Phox/PB1), DnaJ-like, thioredoxin, FBD and F-box, and protein kinase and U-box, indicating varied functions for these proteins. To provide proof-of-concept of the newly identified CC-TPR proteins for interaction with Hsp90, we demonstrated interaction of AtTPR1 and AtTPR2 with AtHsp90 in yeast two-hybrid and in vitro pull down assays. These findings indicate that the in silico approach used here successfully identified in a genome-wide context CC-TPR proteins with potential to interact with Hsp90/Hsp70, and further suggest that the Hsp90/Hsp70 system relies on TPR co-chaperones more than it was previously realized.
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