Seminars

Fall 2016

The seminars are held on Thursdays at 11:30pm in the lecture room GB03 in wing B

(Click on the green bar to find out more about the speaker and the topic)

August 18, 2016 - Dr. Helen Blanchard, Griffith University

Carbohydrate-recognising proteins (lectins) have significant roles in disease progression. Viruses and bacteria often utilise lectins for host-pathogen interactions, facilitating attachment to host cells and subsequent infection. Galectins recognise and bind to carbohydrates during critical stages of their involvement in progressing cancer growth, tumour survival, and promoting metastasis. The design of inhibitors to block lectin function is an important approach to reduce and/or eliminate disease progression but is often challenging due to the inherent nature of carbohydrate-binding sites. Our studies incorporate X-ray crystallographic elucidation of the atomic structures of two lectin-based systems that progress human diseases: the rotavirus spike lectin domain (VP8*) and human galectin-3 –with the latter identified as having key roles in cancers such as lung, breast and the blood cell cancer acute lymphoblastic leukaemia. Our investigation informs on how these proteins interact with particular carbohydrates, giving insight into how they achieve their function, and providing critical information for progressing our structure-based design of potent and selective inhibitors.

Title: Structural insights and challenges in designing inhibitors that target disease-promoting carbohydrate-recognising proteins

September 8, 2016 - Dr. Zongchao Jia, Queens University
Short bio
Following his Ph.D. from University of Saskatchewan in 1992, Dr. Jia did post-doc training in University of Oxford. In 1995 he joined Queen’s University and started its first structural biology program. He has worked on several biologically important systems including protein phosphorylation, calcium-binding proteins and host-pathogen interactions. Thus far he has published ~245 papers including 8 in Nature, Science and Cell. Dr. Jia has received many honors/awards such as NSERC Steacie Fellow and Killam Fellow. He is currently a Tier 1 Canada Research Chair.
 

Title: Structure-guided inhibition of Pseudomonas aeruginosa Type II secretion system

September 15, 2016 - Dr. Joyce Wilson, University of Saskatchewan

Stabilization and efficient accumulation of the Hepatitis C virus genome during an infection requires annealing of a liver specific miRNA, miR-122, to two binding sites on the 5’ terminal sequence of the HCV genome. That miR-122 promote HCV replication is interesting since miRNAs normally bind to the 3’ UTRs of mRNAs and decrease their translation and stability, and rarely promote anything. miR-122 anneals to the HCV genome with a specific annealing pattern and is almost essential for HCV replication. However, HCV RNA accumulation is undetectable in the absence of miR-122 and the null phenotype provides little mechanistic insight. We have developed models of miR-122-independent replication as models to study the role of miR-122. We are using these models to characterize what happens during an infection when miR-122 is absent, and to identify host genes that limit HCV replication in the absence of miR-122.  In addition, we are interested in the specific requirements of the miR-122 binding site sequences in the HCV genome. The HCV 5’ UTR is highly conserved and thought to be intolerant to sequence changes, in part due to its role in binding miR-122. To better understand the role of the multifunctional 5’ terminal sequence in HCV replication we have used siRNAs knockdown and virus escape from knockdown as a mutagenic tool to generate replication competent HCV mutants having point mutations in the 5’ terminal sequence. Our mutagenic studies suggest that this region is actually relatively tolerant to point mutations. Surprisingly, we also found that some mutant viruses had gained the ability to use the mutagenic siRNA as a miR-122 mimic to promote HCV replication. One mutant virus in particular appeared to be dependent on the siRNA and exhibited very little response to miR-122. These findings reveal that neither miR-122 nor its specific annealing pattern with the HCV 5’ UTR are essential for efficient miR-122-like small RNA promotion of HCV replication. We will use these findings to further define the annealing requirements for miR-122, and other small RNA to promote HCV replication.

 

 

Title: HCV replication promotion by miR-122 and other small RNAs

September 22, 2016 - Dr. Scott Napper, University of Saskatchewan

Title: Conformation-Specific Immunotherapy of Prion (and Prion-like) Diseases

September 29, 2016 - Dr. Stephanie Karst, University of Florida
The Karst laboratory investigates norovirus replication, pathogenesis and immunity using a small animal model and a newly developed human norovirus culture system. In both of these systems, commensal bacteria have emerged as a critical regulator of viral infection. Specifically, commensal bacteria direct the intestinal regionalization of murine norovirus infections in mice and significantly influence both the innate and adaptive antiviral immune responses. They also act as a co-factor for human norovirus infection of B cells in vitro. This emerging concept that the intestinal microbiota play a pivotal role in regulating enteric virus infections should ultimately lead to novel preventative and therapeutic approaches.

Title: The Interplay between noroviruses and commensal bacteria

October 6, 2016 - Dr. Jeremy Lee, University of Saskatchewan

Title: Dimer drugs as a treatment for Parkinson's disease. Staying in the loop.

October 13, 2016 - Dr. Dean Chapman, CLS and University of Saskatchewan

Synchrotron facilities supply brilliant light that can be used for a wide variety of research applications to all of the basic sciences as well as agriculture, advanced materials science, environment and health.  This presentation will briefly describe a bit about synchrotron light, the synchrotron, beamlines and types of beamlines as well as the set of beamlines and properties of the Canadian Light Source.  Some examples of biomedical related research at the CLS will be presented.  It should be noted that with most access is via a peer reviewed proposal mechanism.  For non-proprietary or industrial uses there is a cost-recovery fee.  However, for most academic research for which there is an intent to publish, the access is basically FREE (or actually $1 per 8 hour shift).

Title: Biomedical Research Applications at the Canadian Light Source

October 20, 2016 - Dr. Jennifer Cobb, University of Calgary
Dr. Cobb is an Associate Professor in the Departments of Biochemistry & Molecular Biology and Oncology and the co-Lead for Research at the Arnie Charbonneau Cancer Institute. She obtained her PhD from the University of Tennessee in 2000 and trained at the University of Geneva, Switzerland until the end of 2006. In 2007, she opened her own laboratory at the University of Calgary’s Cumming School of Medicine.

Title: The role of Structural Maintenance of Chromosome (SMC) complexes in Genome Stability

November 3, 2016 - Dr. John Gordon, University of Saskatchewan
The Gordon lab’s interest is in the translation of basic immunotherapeutics principles into the clinic. Using allergic diseases as examples, we will examine the roles of natural and induced populations of regulatory dendritic cells (DCreg) in immune tolerance and explore their applications in both mouse models and with the human immune system. The mechanisms by which such DCreg can induce tolerance and the potential for their clinical application will also be addressed

Title: Regulatory dendritic cell therapy: from bench to bedside

November 17, 2016 - Dr. Kerry Bloom, University of North Carolina
The centromere is the region of the chromosome where sister chromatids remain connected in meiosis I and the site of kinetochore assembly. In mammalian cells centromere heterochromatin spans 5-10 Mb of DNA. In budding yeast, each 125 bp centromere is embedded in 50 kb of DNA enriched in cohesin and condensin. Cohesin and condensin promote looping and cross-linking between the pericentromeres of different chromosomes, creating a network of about 800 kb (16 chromosomes x 50 kb) surrounding the spindle. The centromere loops function to stiffen the linkage between sister kinetochores and ensure the fidelity of chromosome segregation.

Title: How the centromere promotes chromosome segregation

November 24, 2016 - Dr. Graham George, University of Saskatchewan - cancelled

Title: TBD

December 1, 2016 - Dr. Eric Arts, University of Western Ontario
Eric J. Arts is Chair of the Department of Microbiology and Immunology at Western University in London, Canada. He also holds a Canada Research Chair in HIV pathogenesis and viral control. Previously he held a position as Professor in the Division of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. He received an honors BSc degree (1990) from Western University followed by a PhD (1994) from McGill University, Montreal, Canada. With support from Health Canada PhD and PDF fellowships, he published >25 research papers with his PhD advisor, Dr. Mark Wainberg at the McGill AIDS Center and with his PDF advisor, Dr. Stuart F.J. LeGrice at CWRU.
His research for the past 16 years described in over 120 publications has focused on HIV-1 fitness, evolution, and virulence in regards to transmission, disease progression, immune escape, drug resistance, and global HIV spread. Since 1998, he has directed the research laboratories at the Joint Clinical Research Centre, Kampala, Uganda and has collaborated with investigators in Zimbabwe, China, Cameroon, Belgium, UK, France, Brazil, and Argentina. His research has been supported by grants from the NIH (NIAID, NICHD, and NHLBI), from the State of Ohio, Merck, and amfAR. He has served as chair and member of the NIH and CIHR grant panel and has reviewed grants for many governments around the world.

Title: HIV in humans: Understanding jump from Chimpanzees to the modern day epidemic

December 6, 2016 - Dr. Jan Rainey, Dalhousie University

Spider wrapping silk is one of the toughest known materials, with the capability to absorb a phenomenal amount of energy per unit mass before failure. In the species Argiope trifasciata, wrapping silk is made up of a protein with a core region of 14 or more concatenated identical 200 amino acid domains. This is spun by the spider into fibres used to wrap prey or eggs. In Escherichia coli, we produce recombinant wrapping silk having 1-4 repetitive domains (referred to as W1-W4). With W2 or larger constructs, fibres may be readily formed either manually or through automated wet-spinning approaches we have developed. The mechanical properties of these fibres are promising, and crudely appear to scale with molecular weight. Through E. coli protein expression, NMR-active isotope enrichment is readily possible. This has allowed us to employ triple-resonance (15N, 13C, and 1H)  and 19F NMR experiments, determining the atomic-resolution structure of W1 and W2, measuring localized motion within the protein, and probing conformational changes. Using Raman spectroscopy, we have also characterized protein secondary structuring in the fibrillar state.  A clear structural transition between the soluble and fibrous states takes place, with NMR spectroscopy providing direct insight into the potential mechanism for this transition. We are currently testing this hypothetical mechanism and are employing our structural understanding of the W unit to rationally modify fibre assembly and properties.

Title:  The molecular features underlying spider wrapping silk toughness.

December 8. 2017 - Dr. Brendan J. Battersby, University of Helsinki

The fundamental defining feature of eukaryotes is membrane bound organelles that possess their own genome with distinct patterns of transmission and inheritance. Mitochondria have two dynamic membranes that enclose a small circular multi-copy genome, which in animals encodes 13 hydrophobic proteins essential for aerobic energy metabolism. All nucleated animal cells contain mitochondria so there must be intracellular communication between these two genomes to sustain a mitochondrial biogenesis program needed cell growth and division. Research from my lab, and a number of other groups, indicates that mitochondrial protein synthesis appears to be actively monitored in the cell. However, there is a clear functional distinction between the absence of protein synthesis from defects that arise during translation elongation as the latter appears to impose a far greater fitness cost to the cell and is linked to inherited human diseases. The 13 proteins synthesized on mitochondrial ribosomes are in excess of the demand needed for de novo assembly of respiratory chain complexes or the ATP synthase. Therefore, to prevent protein over accumulation in the membrane mitochondrial protein synthesis needs to be tightly coupled to proteolytic quality control. Our previous work demonstrated how defects in the quality control de novo mitochondrial proteins leads to aberrant protein accumulation in the mitochondrial inner membrane. This creates a membrane stress that progressively dissipates the mitochondrial membrane potential, which in turn stalls mitochondrial protein synthesis and fragments the mitochondrial network. To elucidate the molecular basis of this mechanism, we focused on the quality control of the mitochondrially synthesized MT-ATP6, which is an essential subunit of the ATP synthase. We demonstrate independent pathways mediate the turnover of de novo MT-ATP6 contingent upon folding of the nascent polypeptide chain. Using a pathogenic nonstop mutation in MT-ATP6, we identify several critical factors and a mechanism needed for the co-translational quality control of this protein that is needed to maintain mitochondrial gene expression and respiratory chain function. We propose this nascent chain surveillance mechanism acts as a sensor to effectively couple the synthesis of mitochondrial proteins to organelle fitness, thus ensuring coordinated assembly of the oxidative phosphorylation complexes from two sets of ribosomes needed for mitochondrial biogenesis.

Title: A balancing act in protein synthesis by two genomes for cell fitness

December 15, 2016 - Dr. Martin Schmeing, McGill University

Dr. T. Martin Schmeing is an Associate Professor, Department of Biochemistry, McGill University, the Associate Director of the McGill Centre for Structural Biology, and the Canada Research Chair in Macromolecular Machines.

Dr. Schmeing first performed research at McGill University, in Dr. Jerry Pelletier’s laboratory during his BSc degree. He then moved to Yale University to perform masters and doctoral research under the supervision of Dr. Thomas Steitz. There, his work focused on the architecture and mechanism of the large ribosomal subunit. Dr. Schmeing then undertook postdoctoral training at the Laboratory of Molecular Biology, Cambridge, UK, with Dr. V. Ramakrishnan. Dr. Schmeing first used cryo-electron microscopy to visualize the first steps of protein synthesis in eukaryotes. He then used X-ray crystallography to provide a complete view of how the fidelity of protein synthesis and tRNA selection is achieved, and resolved longstanding questions pertaining to the mechanism of decoding.                                               

Dr. Schmeing established his own laboratory at McGill in 2010, where he studies nonribosomal peptide synthetases (NRPSs). NRPSs are large microbial enzymes that synthesize their products through amide bond formation between building block monomers (most commonly amino acids). The chemical and biological properties of these compounds often make them useful to society as therapeutics (antibiotics, antivirals, anti-tumours, and immunosuppressants) and as natural green chemicals (agricultural agents, emulsifiers, siderophores, and research tools). Dr. Schmeing’s research focuses on multiple aspects of the structures and functions of NRPSs. Two aspects of particular focus are the catalytic event which links substrate building blocks into amino acid, and into the manner in which these enzymes’ domains and modules work together in a complicated and productive catalytic cycle.

 

Title: Structural insight into megaenzyme nanofactories

January 12, 2017 - Dr. Tom Hobman, University of Alberta
Zika virus (ZIKV) is a mosquito-transmitted human pathogen that has spread to over 50 countries since the 2015 outbreak in Brazil. As a result, millions of human infections occurred and thousands of cases of ZIKV-related birth defects were observed in Brazil alone. Currently, there are no licensed antivirals or vaccines available against the virus. A.aegypti and A. albopictus mosquitoes are the main vectors for ZIKV transmission; the latter species is widespread in North America including regions of Canada that border the US. While ZIKV is already circulating in parts of the US, the risk of vector-borne transmission in Canada is not clear.
However, a significant number of Canadians have contracted ZIKV during travel to endemic countries and it is now well documented that the virus can be transmitted through sexual activity as well as from mother to fetus. ZIKV infection is often subclinical but the demonstrated link to microcephaly in fetuses and more recently Guillain-Barre syndrome in adults has raised the urgency for understanding the molecular mechanisms governing infection and transmission. While a number of vaccine candidates are in development, there are potential challenges to its widespread implementation. As such, the need to understand virus-host interactions and ZIKV pathogenesis remain important issues. Our laboratory is focused on identifying key strategies used by ZIKV to elude host antiviral defences and establish persistent infections.

Title: Persistence and pathogenesis of Zika virus: Clues from virus-host interactions at the cellular level

January 26, 2017 - Dr. James Bardwell, University of Michigan
Dr. Bardwell will describe a new technique that has enabled him to see the multiple conformations assumed by a substrate when bound to a chaperone, and also to watch chaperone-mediated folding at high resolution. He will also examine four of the central questions of chaperone biology: how chaperones rapidly bind to proteins, how the chaperone-client complex is stabilized, how a chaperone can facilitate substrate folding, and what triggers substrate release.

Title: Visualizing Chaperone Mediated Protein folding

February 2, 2017 - Dr. David Cooper, University of Saskatchewan
The porosity within compact (cortical) bone was detected by the very first microscopes.  Today these pores remain key targets of investigation due to their relation to chronic bone loss and related fractures. They are the very ‘pores’ of osteoporosis; However, beyond being just structural liabilities they  provide a powerful window into the dynamic process of bone turn-over known as remodeling.  The remodeling process underlies changes associated with adaptation, aging and disease and thus the spatial distribution, orientation, size and even interconnectivity of cortical pores are all believed to carry mechanical and/or physiological significance.  Deciphering such information has been challenging due to limitations associated with obtaining three-dimensional microstructural data and a near complete lack of direct longitudinal (four-dimensional) data. This presentation provides an overview of efforts by Dr. Cooper’s research group to overcome these hurdles through the use of in vivo synchrotron-based imaging at the Canadian Light Source.

Title: Tracking the Pores of Osteoporosis: Development of in vivo Animal Models at the Canadian Light Source

February 9, 2017 - Dr. David Wishart, U of Alberta -- CANCELLED

Title: CANCELLED

February 16, 2017 - Dr. Kevin Rozwadowski, University of Saskatchewan

DNA recombination during meiosis is the fundamental biological process affecting crop improvement through plant breeding as it controls the frequency of exchange of alleles between donor and recipient genotypes and, thus, the speed of trait introgression and achievement of desired genetic outcomes.  Modulation of recombination frequency can improve the efficiency of plant breeding programs by influencing the number of progeny and generations required to attain a preferred combination of alleles.  To this end, the Rozwadowski lab is investigating the effects of altering the activity of several steps in the recombination pathway to develop technologies to modulate meiotic recombination frequency in crops.  In addition to assessing the effects of canonical recombination proteins, we also seek new candidates to manifest changes in recombination frequency by using molecular, biochemical and genetic approaches.  From a protein interaction screen using as bait RAD51, the eukaryotic RecA homologue mediating DNA homology search, pairing and exchange, we identified the DNA demethylase DEMETER (DME), an epigenetic regulator of imprinted genes.  This presentation will describe efforts to elucidate the possible link of DME to DNA repair responses in the model plant Arabidopsis thaliana, implicating modulation of DNA methylation status as a possible factor influencing homologous recombination.

Title: A possible link between DNA methylation status and homologous recombination revealed by characterisation of DEMETER, a DNA demethylase in plants
March 2, 2017 - John Howland, University of Saskatchewan

According to the Canadian Mental Health Association, 20% of Canadians will experience mental illness at some points during their lives. Although there is strong evidence for genetic causes of some psychiatric disorders, recent studies indicate that environmental factors also play a major role in the development of psychiatric disorders, in particular schizophrenia. One such factor contributing to psychiatric disorders in adulthood is prenatal infection, or exposure to an infection while in utero. My research explores this connection by using rat models. We have recently shown an array of behavioural changes in the offspring of pregnant rats exposed to polyinosinic-polycytidylic acid (polyI:C), a synthetic analogue of double-stranded RNA recognized as a virus by the mammalian immune system. I will discuss on-going experiments in my laboratory designed to assess the relevance of these behavioural changes to psychiatric disorders. By combining immunological research related to infection with that focused on psychiatric disorders, I propose an approach to treating psychiatric disorders that focuses on prevention rather than the treatment of symptoms.

Title: Rodent models of maternal immune activation during pregnancy: effects on the offspring relevant to psychiatric disorders

March 9, 2017 - Chris Eskiw, University of Saskatchewan
Aging affects us all. Is aging inevitable or can it be treated like a disease? We know that reducing caloric intake without inducing malnutrition can increase lifespan whilst also decreasing the occurrence of age-related pathologies such as cardiovascular disease, diabetes and cancer. Recent research now demonstrates that pharmacological agents, such as rapamycin and metformin, may function as mimics of decreased caloric intake, disrupting cellular energy sensing pathways and leading to increased lifespan in several model organisms. Although the biochemical pathways by which these compounds function has been well defined, it is not clear how these compounds impact genome function (gene expression) and organization to promote this. The overall aim of my laboratory is to investigate compounds with known lifespan extension properties and identify changes in genome function and structure. Our aim is also to identify naturally occurring compounds present in the diet with similar properties that can help promote increased health and lifespan. Our current model focuses on normal human fibroblasts as well as fibroblasts from children suffering from the premature aging disease, Hutchinson Gilford progeria syndrome (HGPS) to identify the basic mechanisms mediating increased cellular lifespan at the genomic level.

Title: Better living through chemistry: Impact of caloric restriction mimetics on  genome function to promote increased cellular longevity

March 16, 2017 - John DeCoteau, University of Saskatchewan

The field of oncology has been at the forefront of translating research discovery into improved diagnostics and targeted therapies. Consequently, the use of leading edge technologies, to support the diagnosis and monitoring of cancer patients, is now an essential element of clinical cancer care. The availability of these tools and approaches also creates excellent opportunities to pursue translational cancer research related to hematological malignancies and solid tumors.

 The Advanced Diagnostics Research Laboratory (ADRL) serves to develop, validate, and perform state-of-the-art diagnostic and monitoring tests for cancer patients using new technology platforms such as 10-color flow cytometry and next generation sequencing (NGS). The information emerging from these tests can now be used to improve cancer diagnosis and classification, and identify those cancer patients most likely to benefit from targeted therapies. New monitoring tests, having vastly increased sensitivity compared to standard approaches, are revolutionizing cancer care by allowing clinicians to safely reduce, or cease, potentially toxic therapies in those patients achieving 'deep' remissions, and by detecting early recurrence of cancer so that treatment approaches can be modified before unsalvageable disease progression occurs.

This presentation will outline some of the new diagnostic and monitoring tools available locally to support modern cancer care and translational cancer research.

 

Title: New Pathology Tools to Support Modern Cancer Care and Translational Cancer Research at the Advanced Diagnostics Research Laboratory

March 23, 2017 - Ann-Claude Gingras, University of Toronto
Compartmentalization is essential for all complex forms of life. In eukaryotic cells, membrane-bound organelles, as well as a multitude of protein- and nucleic acid-rich subcellular structures, maintain boundaries and serve as enrichment zones to promote and regulate protein function. Consistent with the critical importance of these boundaries, alterations in the machinery that mediate protein transport between these compartments is linked to a number of diverse diseases. Understanding the composition of each cellular “compartment” remains a challenging task. Classically, both microscopy and organellar purifications have been employed for identifying the composition of these structures, but these approaches have limitations, notably in resolution for standard high-throughput fluorescence microscopy and in the difficulty in purifying some of the structures (e.g. p-bodies) for approaches based on biochemical isolations.
 
Prompted by the recent implementation in vivo biotinylation approaches such as BioID, we report here the systematic mapping of the composition of various subcellular structures, using as baits proteins that are well-characterized markers for a specified location. We defined how relationships between “prey” proteins detected through this approach can help understanding the protein organization inside a cell. We will discuss our low-resolution map of a human cell containing major organelles and non-membrane bound structures, but also a higher resolution map of RNA-containing cellular structures, including the p-bodies and the stress granules that regulate mRNA stability. This will be presented alongside new computational resources that will help the scientific community to make use of our dataset.

Title: A physical map of a human cell

March 30, 2017 - Chris Rochet - Purdue University
The post-mortem brains of individuals with Parkinson's disease (PD) and other synucleinopathy disorders are characterized by the presence of aggregated forms of the presynaptic protein alpha-synuclein (aSyn). Understanding the molecular mechanism of aSyn aggregation is essential for the development of neuroprotective strategies to treat these diseases. A focus of our research has been to understand how interactions between aSyn and phospholipid membranes influence the protein's aggregation and toxicity to dopaminergic neurons. We have found that aSyn mutants linked to familial PD populate an exposed, membrane-bound conformer in which the central hydrophobic region is dissociated from the bilayer to a greater extent than in the case of wild-type aSyn.
The familial mutants have a greater propensity to undergo membrane-induced aggregation, trigger vesicle disruption, and elicit neurotoxicity compared to the wild-type protein. Moreover, mouse aSyn, which differs from human aSyn by 7 mismatches, is less toxic than the human protein in an animal model of PD and has a reduced propensity to undergo membrane-induced aggregation and trigger vesicle disruption. Endosulfine-alpha, a protein that interacts specifically with membrane-bound aSyn, alleviates membraneinduced aggregation, membrane permeabilization, and neuronal cell death elicited by human familial aSyn mutants. Short peptides that bind membrane-associated aSyn exhibit similar protective effects. Our results provide strong support for the idea that aSyn aggregation at membrane surfaces plays a key role in aSyn neurotoxicity in PD, and they suggest that interfering with membrane-induced aSyn self-assembly could be a therapeutic strategy to alleviate neurodegeneration in the brains of patients.

Title: Inhibition of membrane-induced alpha-synuclein aggregation as a neuroprotective strategy in Parkinson’s disease

April 6, 2017 - Erique Lukong, University of Saskatchewan

Breast cancer is a heterogeneous disease that can be stratified based on the expression of molecular markers such the estrogen receptor, progesterone receptor and epidermal growth factor receptor 2. The movement toward targeted therapies has led to the development of drugs that block the function of some of these receptors as well as proteins associated with cancer formation and progression, including some non-receptor tyrosine kinases. Breast tumor kinase (BRK) is a non-receptor tyrosine kinase that has been shown to be overexpressed in human breast tumors and breast cancer cell lines, compared to cells of the normal mammary gland. The overexpression of BRK has been shown to sensitize mammary epithelial cells to mitogenic signaling and to promote cell proliferation and tumor formation. However, there are still several unanswered questions about the cellular and physiological roles of BRK and its clinical implications in breast cancers. I will discuss our data highlighting the role of BRK in breast tumor progression, its differential expression in breast cancer subtypes and a novel mechanism for its upregulation, as well as the potential clinical significance of BRK overexpression in breast cancer.

Dr. Kiven Erique Lukong received his Ph.D. degree in biochemistry from the University of Montreal in Canada and pursued his post-doctoral training first at Harvard Medical School, U.S.A. and later at McGill University (Canada). He is currently an Associate Professor in the Department of Biochemistry at the University of Saskatchewan (U of S, Canada) since 2009 and a member of the Cancer Research Cluster at the U of S. Since beginning his independent academic career at the U of S, Dr. Lukong has obtained career awards from the Saskatchewan Health Research Foundation (SHRF, Top New investigator 2010) and from the Canadian Institutes of Health Research (CIHR, New investigator salary award). Dr. Lukong’s research broadly involves elucidating the signaling mechanisms that control growth of normal and cancer cells.  His lab is investigating the cellular and physiological roles, and the mechanisms of action and modes of regulation of the breast tumor kinase (BRK) family of non-receptor tyrosine kinases in breast cancer and glioblastoma. The Lukong lab is also characterizing the diagnostic, prognostic and therapeutic potential of the BRK family proteins in breast cancer. Dr. Lukong holds or has held funding from SHRF, CIHR and the Canadian Breast Cancer Foundation. 

Title: Breast tumor kinase: Potential clinical implications in breast cancers

April 21, 2017 - Rick Wozniak, University of Alberta

In all eukaryotic cells, the genome is enclosed by the nuclear envelope membrane (NE), which forms the surface of the roughly spherical nucleus. Extending across the NE are massive structures termed nuclear pore complexes (NPCs). While the most established function of NPCs is the regulation of nucleocytoplasmic transport, it has long been proposed that NPCs also function to organize chromatin at the NE and control the expression of associated genes. We have studied the interactions of NPC proteins (termed nucleoporins) with chromatin in the yeast model system. In a recent study (Van de Vosse et. al., Cell. 2013), we showed that the nucleoporin Nup170 binds to subtelomeric chromatin through its interactions with the silencing factor Sir4. Furthermore, we showed that Nup170 is required for the association of subtelomeric chromatin with the NE and for maintaining many subtelomeric genes in a silenced state. Our further analysis of the Nup170-Sir4 protein complex has now revealed that the Nup170 bound to Sir4 is not part of NPCs, but rather a derivative of NPCs consisting of Nup170 and specific subsets of nucleoporins that contribute to the core scaffold subunits of the NPC. However, unlike holo-NPCs, this Sir4-associated nucleoporin complex (termed the Snup complex) lacks numerous other nucleoporins including those that contribute to the cytoplasmic filaments and the nuclear basket of NPCs. On the basis of our data, we conclude that the Snup complex is a previously unidentified derivative of NPCs distinct from holo-NPCs, and we propose that it functions in subtelomeric chromatin organization and NE-tethering.  

Title: Nuclear pore complex proteins as regulators of chromatin organization

May 4, 2017 - Thierry Vernet, Institut biologie structurale, CNRS, Grenoble

Despite efficient vaccines and antibiotic treatments Streptococcus pneumonia (the pneumococcus) remains a major human pathogen claiming the life of over 1.5 million people worldwide yearly. This Gram-positive bacterium adheres to the upper respiratory track owing to surface pili. This fibrous virulence factor linked to bacterial surface peptidoglycan is composed of three structural proteins: pilins RrgA, B and C, involved in adhesion, fiber architecture and attachment to the cell wall respectively. Three transpeptidase enzymes, sortases SrtC-1, SrtC-2 and SrtC-3, mediate the assembly of the pilus. The substrate specificity of the sortases for the pilins has been determined using combinations of co-expression of sortases and pilins in E. coli. The remarkable stability of the pilus originates from the presence of unusual isopeptide bonds within each pilins. From the crystallographic structure of RrgA we have derived two protein fragments Jo (10.5 kDa) and In (15.1 kDa) able to form spontaneously in vitro and in vivo a covalent complex (JoIn). Using this Bio Molecular Welding process we have derived biotech applications related to the production of polyclonal antibodies against membrane proteins, nanoassembly and cell-surface labelling.


Thierry Vernet PhD in molecular biology and biochemistry (University Louis Pasteur in Strasbourg, France in 1981. He moved to Canada from 1981 to 1994 to work in Ottawa and Montreal as a research officer for the National Research Council of Canada on microbial toxins and protease engineering.
He is now head of the Pneumococcus Group and in charge of technology transfer at the Institute for Structural Biology in Grenoble (CEA; CNRS; U. Grenoble Alpes) where he works with his collaborators on the biology of the pneumococcus with a particular emphasis on the analysis of the mechanisms of cell wall synthesis and morphogenesis, resistance to antibiotics, bacterial division and the role of virulence factors. His laboratory hosts the RoBioMol service platform of automates dedicated to high through put molecular biology and recombinant soluble and membrane protein production. He has published over 130 refereed papers, reviews and book chapters and is member of various expert committees in France and abroad.

Title: The pneumococcus pilus: its assembly, structure and biotech applications