Digital Commons Network^™

Domains Of Stip1 Responsible For Regulating Prpc-Dependent Amyloid-Β Oligomer Toxicity., Andrzej Maciejewski, Valeriy G Ostapchenko, Flavio H Beraldo, Vania F Prado, Marco A M Prado, Wing-Yiu Choy

Biochemistry Publications

Soluble oligomers of amyloid-beta peptide (AβO) transmit neurotoxic signals through the cellular prion protein (PrP(C)) in Alzheimer's disease (AD). Secreted stress-inducible phosphoprotein 1 (STIP1), an Hsp70 and Hsp90 cochaperone, inhibits AβO binding to PrP(C) and protects neurons from AβO-induced cell death. Here, we investigated the molecular interactions between AβO and STIP1 binding to PrP(C) and their effect on neuronal cell death. We showed that residues located in a short region of PrP (90-110) mediate AβO binding and we narrowed the major interaction in this site to amino acids 91-100. In contrast, multiple binding sites on STIP1 (DP1, TPR1 and TPR2A) …

Molecular Pathways: Emergence Of Protein Kinase Ck2 (Csnk2) As A Potential Target To Inhibit Survival And Dna Damage Response And Repair Pathways In Cancer Cells, Adam J. Rabalski, Laszlo Gyenis, David W. Litchfield

Biochemistry Publications

©2016 AACR. Protein kinase CK2 (designated CSNK2) is a constitutively active protein kinase with a vast repertoire of putative substrates that has been implicated in several human cancers, including cancer of the breast, lung, colon, and prostate, as well as hematologic malignancies. On the basis of these observations, CSNK2 has emerged as a candidate for targeted therapy, with two CSNK2 inhibitors in ongoing clinical trials. CX-4945 is a bioavailable small-molecule ATP-competitive inhibitor targeting its active site, and CIGB-300 is a cell-permeable cyclic peptide that prevents phosphorylation of the E7 protein of HPV16 by CSNK2. In preclinical models, either of these …

Mtorc1 And Ck2 Coordinate Ternary And Eif4f Complex Assembly, Valentina Gandin, Laia Masvidal, Marie Cargnello, Laszlo Gyenis, Shannon Mclaughlan, Yutian Cai, Clara Tenkerian, Masahiro Morita, Preetika Balanathan, Olivier Jean-Jean, Vuk Stambolic, Matthias Trost, Luc Furic, Louise Larose, Antonis E. Koromilas, Katsura Asano, David Litchfield, Ola Larsson, Ivan Topisirovic

Biochemistry Publications

Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role …

A Unified Analytic Framework For Prioritization Of Non-Coding Variants Of Uncertain Significance In Heritable Breast And Ovarian Cancer, Eliseos J. Mucaki, Natasha G. Caminsky, Ami M. Perri, Ruipeng Lu, Alain Laederach, Matthew Halvorsen, Joan H. M. Knoll, Peter K. Rogan

Biochemistry Publications

Background

Sequencing of both healthy and disease singletons yields many novel and low frequency variants of uncertain significance (VUS). Complete gene and genome sequencing by next generation sequencing (NGS) significantly increases the number of VUS detected. While prior studies have emphasized protein coding variants, non-coding sequence variants have also been proven to significantly contribute to high penetrance disorders, such as hereditary breast and ovarian cancer (HBOC). We present a strategy for analyzing different functional classes of non-coding variants based on information theory (IT) and prioritizing patients with large intragenic deletions.

Methods

We captured and enriched for coding and non-coding variants …

Cost-Effectiveness Of Using A Gene Expression Profiling Test To Aid In Identifying The Primary Tumour In Patients With Cancer Of Unknown Primary., M B Hannouf, E Winquist, S M Mahmud, M Brackstone, S Sarma, G Rodrigues, P Rogan, J S Hoch, G S Zaric

Biochemistry Publications

We aimed to investigate the cost-effectiveness of a 2000-gene-expression profiling (GEP) test to help identify the primary tumor site when clinicopathological diagnostic evaluation was inconclusive in patients with cancer of unknown primary (CUP). We built a decision-analytic-model to project the lifetime clinical and economic consequences of different clinical management strategies for CUP. The model was parameterized using follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. The 2000-GEP-based strategy compared to current clinical practice resulted in an incremental cost-effectiveness ratio (ICER) of $44,151 per quality-adjusted life years (QALY) gained. The total annual-budget …

Automated Discrimination Of Dicentric And Monocentric Chromosomes By Machine Learning-Based Image Processing., Yanxin Li, Joan H Knoll, Ruth C Wilkins, Farrah N Flegal, Peter K Rogan

Biochemistry Publications

Dose from radiation exposure can be estimated from dicentric chromosome (DC) frequencies in metaphase cells of peripheral blood lymphocytes. We automated DC detection by extracting features in Giemsa-stained metaphase chromosome images and classifying objects by machine learning (ML). DC detection involves (i) intensity thresholded segmentation of metaphase objects, (ii) chromosome separation by watershed transformation and elimination of inseparable chromosome clusters, fragments and staining debris using a morphological decision tree filter, (iii) determination of chromosome width and centreline, (iv) derivation of centromere candidates, and (v) distinction of DCs from monocentric chromosomes (MC) by ML. Centromere candidates are inferred from 14 image …

Prioritizing Variants In Complete Hereditary Breast And Ovarian Cancer (Hboc) Genes In Patients Lacking Known Brca Mutations., Natasha G Caminsky, Eliseos J Mucaki, Ami M Perri, Ruipeng Lu, Joan H M Knoll, Peter K Rogan

Biochemistry Publications

BRCA1 and BRCA2 testing for Hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including non-coding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict and prioritize non-coding variants of uncertain significance (VUS) in regulatory, coding, and intronic regions based on changes in binding sites in these genes. Besides mRNA splicing, IT provides a common …

Gar22Β Regulates Cell Migration, Sperm Motility, And Axoneme Structure, Ivonne Gamper, David Fleck, Meltem Barlin, Marc Spehr, Sara El Sayad, Henning Kleine, Sebastian Maxeiner, Carmen Schalla, Gülcan Aydin, Mareike Hoss, David W. Litchfield, Bernhard Lüscher, Martin Zenke, Antonio Sechi

Biochemistry Publications

© 2016 Gamper et al. Spatiotemporal cytoskeleton remodeling is pivotal for cell adhesion and migration. Here we investigated the function of Gas2-related protein on chromosome 22 (GAR22β), a poorly characterized protein that interacts with actin and microtubules. Primary and immortalized GAR22β-/- Sertoli cells moved faster than wild-type cells. In addition, GAR22β-/- cells showed a more prominent focal adhesion turnover. GAR22β overexpression or its reexpression in GAR22β-/- cells reduced cell motility and focal adhesion turnover. GAR22β-actin interaction was stronger than GAR22β-microtubule interaction, resulting in GAR22β localization and dynamics that mirrored those of the actin cytoskeleton. Mechanistically, GAR22β interacted with the regulator …

Genomic Signatures For Paclitaxel And Gemcitabine Resistance In Breast Cancer Derived By Machine Learning., Stephanie N Dorman, Katherina Baranova, Joan H M Knoll, Brad L Urquhart, Gabriella Mariani, Maria Luisa Carcangiu, Peter K Rogan

Biochemistry Publications

Increasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients. Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n = 31 genes) or gemcitabine (n = 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression …