Competition Results: Lap-Chee Tsui Publication Award (2014)
The Canadian Institutes of Health Research-Institute of Genetics (CIHR-IG) is pleased to announce the Lap-Chee Tsui Publication Award (2014) recipients and finalists, a prize for exceptional trainee-conducted research within the CIHR-IG's mandate.
CIHR-IG established the award to honour one of Canada's greatest researchers, Dr. Lap-Chee Tsui, whose discovery of the gene for cystic fibrosis was a milestone in human genetic disease research.
Joint Recipients - Biomedical research
Amber L. Couzens (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital)
Amber L. Couzens, James D. R. Knight, Michelle J. Kean, Guoci Teo, Alexander Weiss, Wade H. Dunham, Zhen-Yuan Lin, Richard D. Bagshaw, Frank Sicheri, Tony Pawson, Jeffrey L. Wrana, Hyungwon Choi, Anne-Claude Gingras. (2013). Protein Interaction Network of the Mammalian Hippo Pathway Reveals Mechanisms of Kinase-Phosphatase Interactions. Science Signaling, 6(302): rs15.
Callista Yee (McGill University)
Callista Yee, Wen Yang, and Siegfried Hekimi. (2014). The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity Response to Mitochondrial ROS in C. elegans. Cell, 157(4): 897-909.
Recipient - Clinical, health services, population health, or genetic ethical, legal and social issues research
Pawel Buczkowicz (University of Toronto)
Pawel Buczkowicz, Christine Hoeman, Patricia Rakopoulos, Sanja Pajovic, Louis Letourneau, Misko Dzamba, Andrew Morrison, Peter Lewis, Eric Bouffet, Ute Bartels, Jennifer Zuccaro, Sameer Agnihotri, Scott Ryall, Mark Barszczyk, Yevgen Chornenkyy, Mathieu Bourgey, Guillaume Bourque, Alexandre Montpetit, Francisco Cordero, Pedro Castelo-Branco, Joshua Mangerel, Uri Tabori, King Ching Ho, Annie Huang, Kathryn R Taylor, Alan Mackay, Anne E Bendel, Javad Nazarian, Jason R Fangusaro, Matthias A Karajannis, David Zagzag, Nicholas K Foreman, Andrew Donson, Julia V Hegert, Amy Smith, Jennifer Chan, Lucy Lafay-Cousin, Sandra Dunn, Juliette Hukin, Chris Dunham, Katrin Scheinemann, Jean Michaud, Shayna Zelcer, David Ramsay, Jason Cain, Cameron Brennan, Mark M Souweidane, Chris Jones, C David Allis, Michael Brudno, Oren Becher & Cynthia Hawkins. (2014). Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nature Genetics, 46(5): 451-6.
Gopinath Sutendra (University of Oxford)
Gopinath Sutendra, Adam Kinnaird, Peter Dromparis, Roxane Paulin, Trevor H. Stenson, Alois Haromy, Kyoko Hashimoto, Nancy Zhang, Eric Flaim, and Evangelos D. Michelakis. (2014). A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation. Cell, 158(1): 84-97.
Juan Pablo Lopez (McGill University)
Juan Pablo Lopez, Raymond Lim, Cristiana Cruceanu, Liam Crapper, Caroline Fasano, Benoit Labonte, Gilles Maussion, Jennie P Yang, Volodymyr Yerko, Erika Vigneault, Salah El Mestikawy, Naguib Mechawar, Paul Pavlidis & Gustavo Turecki. (2014). miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nature Medicine, 20(7): 764-8.
Mohamed Soliman (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital)
Mohamed A. Soliman, Anas M. Abdel Rahman, Dudley A. Lamming, Kivanç Birsoy, Judy Pawling, Maria E. Frigolet, Huogen Lu, George Fantus, Adrian Pasculescu, Yong Zheng, David M. Sabatini, James W. Dennis, Tony Pawson. (2014). The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism. Science Signaling, 7(313): ra17.
A total of 28 nominations were received, 22 in biomedical research and 6 in clinical, health services, population health, and genetic ethical, legal and social issues research. We would like to take this opportunity to thank all the nominators for their interest in this program and all the nominees for their outstanding contribution to genetic research.
For details regarding the next competition round please visit the CIHR-IG website in summer 2015.
Paul Lasko, PhD
CIHR Institute of Genetics
Protein Interaction Network of the Mammalian Hippo Pathway Reveals Mechanisms of Kinase-Phosphatase Interactions
The organs in our body are composed of cells that are constantly receiving signals from their outside environment, and responding to them by adapting their behavior in various ways. The Hippo pathway is a system of proteins that functions to regulate organ size. This is achieved by proteins controlling when a cell grows and divides or proceeds to programmed cell death. The Hippo pathway can be regulated by a variety of stimuli including pharmacological treatments. Here, we show the protein-protein interactions established by the Hippo pathway proteins in the presence and absence of a treatment that inhibits a class of enzymes known as phosphatases. We identified 749 protein interactions, including 599 previously unrecognized interactions, and demonstrated that several interactions with phosphatases were dependent on the protein modification known as phosphorylation. We further show the phosphorylation dependent interaction between a protein known as MST1 with a phosphatase complex known as STRIPAK (striatin-interacting phosphatase and kinase complex). SLMAP, a component of the STRIPAK complex, required a protein domain known to bind phosphorylation, in order to interact with MST1. Striking changes in the associations established by the adaptor protein, MOB1 were also noted following phosphatase inhibition. These phosphorylation-dependent protein interactions were found to require a binding-pocket on MOB1, where changes to the sequence of this pocket resulted in the loss of phospho-dependent interactions with MST1 and the PP6 phosphatase complex. Collectively, our results indicated that changes in phosphorylation orchestrate interactions between the two classes of enzymes that regulate phosphorylation: the kinases and phosphatases, thus providing a putative mechanism for Hippo pathway regulation.
The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity Response to Mitochondrial ROS in C. elegans
Signalling by mitochondria (the power house of the cell) has been previously shown to play a role in the aging process. As part of normal respiration, proteins in the mitochondria produce low levels of free radicals. Free radicals have the ability to cause permanent damage to the cell. It has been postulated that production of free radicals leads to damage of mitochondrial proteins and subsequently generation of increased levels of free radicals. Over time, this cycle leads to an accumulation of damage and is thought to be a primary cause of aging. As a result, anti-oxidants have been marketed as a means to prevent aging although no empirical data exists to confirm their effect. It has been shown recently through genetic experiments that free radicals may be beneficial and act as signals to prolong lifespan. We have previously generated mutations in the worm C. elegans that result in animals with defective mitochondria. These defective mitochondria produce an increased amount of free radicals. Animals carrying these mutations experience an extremely slow rate of aging. However, treatment of these animals with anti-oxidants abolishes their extended longevity. Using genetics, we were able to determine that this free radical signalling acts through the intrinsic apoptotic pathway, a pathway conserved from worms to humans. Apoptosis, a type of cell suicide, is normally executed in response to damage or to protect the organism if a cell has been compromised. Interestingly, activation of this pathway by free radicals does not induce cell death, but instead initiates a unique defence mechanism that promotes survival.
Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain cancer that arises in children in a region of the brainstem called the pons. There is no effective treatment and this cancer has a near 100% fatality. The failure of most therapies can be attributed to the delicate location of this tumour, which eliminates surgery as a means of treatment, and assumptions that the biology and genetics of DIPG are similar to adult high-grade astrocytomas such as glioblastoma (GBM). Through integration of whole-genome and whole-exome sequencing, DNA methylation, gene expression and copy number profiling, DIPGs were shown to comprise three molecularly distinct subgroups (H3-K27M, Silent and MYCN) and harbour mutations in a new cancer gene, ACVR1. Mutations in ACVR1 occurred in 20% of DIPG and turned on the activin signalling pathway resulting in phosphorylation of SMAD proteins and an increased expression of ID1 and ID2 genes.
The three molecular subgroups each had unique genetic features. The H3-K27M subgroups had p.Lys27Met mutations in histone H3.3 (H3F3A) or H3.1 (HIST1H3B and HIST1H3C), TP53 mutations, alternative lengthening of telomeres (ALT), and unstable genomes with many copy number changes. Tumours in the Silent subgroup had silent genomes with few mutations, structural rearrangements or copy number alterations. The MYCN subgroup had no recurrent mutations but had recurrent high level MYCN and ID2 DNA amplifications caused by catastrophic chromosome shattering, called chromothripsis, on chromosome 2p. These findings highlight clinically relevant subgroups of DIPG and reveal new therapeutic targets for this incurable paediatric cancer.
A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation
Epigenetic regulation of gene expression is important for many physiologic or pathologic conditions, like embryonic development or cancer progression, respectively. One of the well-characterized epigenetic modifications is the acetylation of histones. By neutralizing the positive charges of lysine residues on histone tails, acetylation promotes the relaxation of DNA, necessary for replication and active gene transcription. In eukaryotes, the biosynthesis of acetyl-coenzyme A (CoA), the substrate for histone acetylation, in the nucleus remains incompletely understood. We show, for the first time, that all of the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC), important for the generation of acetyl-CoA for the Krebs' Cycle, are also present in the nucleus of mammalian cells. Furthermore, we show that nuclear PDC is important for the generation of acetyl-CoA for histone acetylation resulting in increased gene expression of many cell cycle proteins, promoting cell cycle progression in cancer. This is one of the first studies to implicate metabolism with epigenetics. The implications of this work are broad as the acetyl-CoA generated from nuclear PDC and subsequent histone acetylation may be important in a variety of epigenetic conditions, like neurodegenerative, myocardial and inflammatory diseases or cancer.
miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment
The goal of pharmacogenetic approaches in psychiatry is to identify clinically meaningful predictors of drug response and side effect burden. Given the clinical heterogeneity and prognostic uncertainty associated with most psychiatric disorders, the concept of personalized pharmacogenetic treatment holds considerable promise. To date, however studies in psychiatry have not yielded compelling results and the only promising data comes from animal studies. Our study was the first to ever show in humans, a consistent microRNA dysregulation in postmortem brain tissue and blood samples from individuals suffering from depression. Our work indicates that miR-1202, a primate-specific and brain enriched microRNA, is differentially expressed in individuals suffering with depression, and predicts antidepressant treatment response. Furthermore, miR-1202 regulates the expression of a gene encoding the metabotropic glutamate receptor-4 (GRM4), indicating a potential disease mechanism and therapeutic target. The major impact of this publication is the identification of a new molecular target for antidepressant treatment. It also raises the question of whether microRNAs may have a role as biomarkers for treatment response in depression, as this has the potential to lead to new and better therapeutic options for major depressive disorder. Furthermore, our results indicate that peripheral blood cells represent a suitable tissue to examine epigenetic processes relevant to major depressive disorder and response to antidepressant treatment. This study highlights the role of miRNAs in neuropsychiatric disorders, and provides important steps in the development of early diagnostic tools, preventive strategies, and effective pharmacological treatment for mood disorders.
The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism
Cell growth and metabolism are tightly controlled processes in our cells. When these functions are disturbed, diseases such as cancer and diabetes occur. We found a unique role for an adaptor protein named p66Shc in regulating glucose metabolism and cell growth. This report could lay the foundation for future studies to target adaptor proteins in cancer and diabetes therapy.
Proteins are functional units of cells that assemble in a precise manner to control cellular processes. Specifically, adapter proteins act as linkers or switches to fine tune cellular functions. Mice deficient in p66Shc show improved glucose tolerance and are resistant to the development of obesity and diabetes. We found that silencing the adaptor protein p66Shc in cells, enhances not only glucose metabolism, but also the metabolism of molecules involved in the making the cells building blocks, resulting in overall increased cell growth.
Thus, p66Shc may have evolved to be a switch that responds to nutrient availability. This role for p66Shc as a sensor of energy levels appears to be unique to higher level organisms. The gene responsible for p66Shc protein expression is relatively new by evolution standards, as it is not seen in species other than vertebrates. Simply stated, p66Shc acts to suppress insulin signaling and energy metabolism when glucose levels are high, as in the case of diabetes.
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