Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

The multi-subunit eEF1 complex plays a crucial role in de novo protein synthesis. The central functional component of the complex is eEF1A, which occurs as two independently encoded variants with reciprocal expression patterns: whilst eEF1A1 is widely expressed, eEF1A2 is found only in neurons and muscle. Heterozygous mutations in the gene encoding eEF1A2, EEF1A2, have recently been shown to cause epilepsy, autism, and intellectual disability. The remaining subunits of the eEF1 complex, eEF1Bα, eEF1Bδ, eEF1Bγ, and valyl-tRNA synthetase (VARS), together form the GTP exchange factor for eEF1A and are ubiquitously expressed, in keeping with their housekeeping role. However, mutations in the genes encoding these subunits EEF1B2 (eEF1Bα), EEF1D (eEF1Bδ), and VARS (valyl-tRNA synthetase) have also now been identified as causes of neurodevelopmental disorders. In this review, we describe the mutations identified so far in comparison with the degree of normal variation in each gene, and the predicted consequences of the mutations on the functions of the proteins and their isoforms. We discuss the likely effects of the mutations in the context of the role of protein synthesis in neuronal development.

/pdf/the-role-of-translation-elongation-factor-eef1-subunits-in-1s2o9xoxjx.pdf

The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders.

Purpose

Patients with systemic lupus erythematosus (SLE) frequently develop lupus nephritis (LN), a complication frequently leading to end stage kidney disease. Immune complex deposition in the glomerulus is central to the development of LN. Using a targeted proteomic approach, we tested the hypothesis that autoantibodies targeting glomerular antigens contribute to the development of LN.



Experimental design

Human podocyte and glomerular proteins were separated by SDS-PAGE and immunoblotted with sera from SLE patients with and without LN. The regions of those gels corresponding to reactive bands observed with sera from LN patients were analyzed using LC-MS/MS.



Results

LN reactive bands were seen at approximately 50 kDa in podocyte extracts and between 36 and 50 kDa in glomerular extracts. Those bands were analyzed by LC-MS/MS and 102 overlapping proteins were identified. Bioinformatic analysis determined that 36 of those proteins were membrane associated, including a protein previously suggested to contribute to glomerulonephritis and LN, annexin A2. By ELISA, patients with proliferative LN demonstrated significantly increased antibodies against annexin A2.



Conclusion and clinical relevance

Proteomic approaches identified multiple candidate antigens for autoantibodies in patients with LN. Serum antibodies against annexin A2 were significantly elevated in subjects with proliferative LN, validating those antibodies as potential biomarkers.

Autoantibodies targeting glomerular annexin A2 identify patients with proliferative lupus nephritis.

Vaccination with Eimeria tenella elongation factor-1α recombinant protein induces protective immunity against E. tenella and E. maxima infections.

Targeted delivery of siRNAs against hepatocellular carcinoma-related genes by a galactosylated polyaspartamide copolymer

The question as to why a protein exerts oncogenic properties is answered mainly by well-established ideas that these proteins interfere with cellular signaling pathways. However, the knowledge about structural and functional peculiarities of the oncoproteins causing these effects is far from comprehensive. The 97.5% homologous tissue-specific A1 and A2 isoforms of mammalian translation elongation factor eEF1A represent an interesting model to study a difference between protein variants of a family that differ in oncogenic potential. We propose that the different oncogenic impact of A1 and A2 might be explained by differences in their ability to communicate with their respective cellular partners. Here we probed this hypothesis by studying the interaction of eEF1A with two known partners - calmodulin and actin. Indeed, an inability of the A2 isoform to interact with calmodulin is shown, while calmodulin is capable of binding A1 and interferes with its tRNA-binding and actin-bundling activities in vitro. Both A1 and A2 variants revealed actin-bundling activity; however, the form of bundles formed in the presence of A1 or A2 was distinctly different. Thus, a potential inability of A2 to be controlled by Ca2+-mediated regulatory systems is revealed.

/pdf/comparison-of-the-ability-of-mammalian-eef1a1-and-its-3lt93m4onr.pdf

Comparison of the ability of mammalian eEF1A1 and its oncogenic variant eEF1A2 to interact with actin and calmodulin.

An investigation into orientation preferences shown by actin fibres within ex-situ actin as imaged by Atomic Force Microscopy (AFM) is described. Actin is a primary cytoskeletal component and is believed to play a vital role in cell structure. Actin structure images measured by AFM were analysed using automated pre-processing steps. These steps were identical for the production of an initial binary image, which was then processed by both Hough transformation and thinning. Results obtained question the validity of using the Hough transform approach, as bias could not easily be eliminated, and hence the Hough transform method was deemed to be unsuitable for this application and instead the thinning technique was used to identify and locate actin orientation within the AFM images. The results show that polymerised ex-situ actin fibres appears to display a bimodal distribution of orientation, with a 90 degree separation, with a significant co-efficient of bimodality of 0.656.

/pdf/analysis-of-microscopy-and-reconstructive-images-for-38sa15a71b.pdf

Analysis of microscopy and reconstructive images for applications in medicine and biology

Many diseases including cancer are associated with a disorganised cytoskeleton. The process of characterising how cytoskeletal disorganisation affects the mechanical properties of cells offers the potential to develop new drugs and treatment regimes that may exploit mechanical weakness in cells and tissues. This work investigated the role of actin associated proteins, namely tropomyosin 1 (tpm1p) and mitochondrial distribution and morphology protein 20 (mdm20p), on the mechanical and morphological properties of yeast cells. For the first time it was shown that deletion of both the TPM1 and MDM20 genes resulted in a decrease in Young’s modulus when compared to the wild-type cells. The deletion strains appeared to have aberrant cell walls when compared to the wild-type strain and also appeared to have lost the characteristic elliptical morphology that is normally exhibited by yeast. Deletion of the TPM1 gene resulted in a significant increase in mean conjugate cell diameter when compared to the wild-type cells, however deletion of the MDM20 gene did not have any significant effect upon the mean conjugate diameter of the yeast cells.

Deletion of the TPM1 and MDM20 Genes Affect theMechanical and Structural Properties of Yeast Cells

Actin bundling and polymerisation properties of eukaryotic elongation factor 1 alpha (eEF1A), histone H2A–H2B and lysozyme in vitro

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Comparison of the ability of mammalian eEF1A1 and its oncogenic variant eEF1A2 to interact with actin and calmodulin.

Analysis of microscopy and reconstructive images for applications in medicine and biology

Deletion of the TPM1 and MDM20 Genes Affect theMechanical and Structural Properties of Yeast Cells

Actin bundling and polymerisation properties of eukaryotic elongation factor 1 alpha (eEF1A), histone H2A–H2B and lysozyme in vitro