The Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada was established under the name of the Samuel Lunenfeld Research Institute in 1985 by an endowment from the Lunenfeld and Kunin families. On June 24, 2013 Larry and Judy Tanenbaum have made a transformative $35 million gift in support of research at the Mount Sinai Hospital. In recognition of the gift, the Institute was renamed the Lunenfeld-Tanenbaum Research Institute. It comprises 36 principal investigators, has a budget of C$90 million , has over 200 trainees and approximately 600 staff. The Institute conducts research into various forms of cancer , neurological disorders and brain illnesses, women’s and infants’ health, diabetes, developmental biology, stem cell biology and tissue regeneration, mouse models of human disease, genomic medicine and systems biology. The Institute has 100,000 sq ft of space and is split between the main hospital and the Joseph and Wolf Lebovic Health Complex.The founding director was Dr. Louis Siminovitch , followed by Dr. Alan Bernstein , Drs. Janet Rossant and Anthony Pawson , Dr. Anthony Pawson and Dr. James Woodgett . Researchers are supported by the Mount Sinai Hospital Foundation, donors and external funding sources including the Canadian Institutes of Health Research, Canadian Cancer Society, Terry Fox Foundation, National Institutes of Health and Genome Canada. Wikipedia.
Jackson S.P.,University of Cambridge |
Durocher D.,Samuel Lunenfeld Research Institute |
Durocher D.,University of Toronto
Molecular Cell | Year: 2013
Ubiquitylation and sumoylation, the covalent attachment of the polypeptides ubiquitin and SUMO, respectively, to target proteins, are pervasive mechanisms for controlling cellular functions. Here, we summarize the key steps and enzymes involved in ubiquitin and SUMO conjugation and provide an overview of how they are crucial for maintaining genome stability. Specifically, we review research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels. In addition to providing key insights into the control and importance of DNA repair and associated processes, such work has established paradigms for regulatory control that are likely to extend to other cellular processes and that may provide opportunities for better understanding and treatment of human disease. © 2013 Elsevier Inc.
Zhang W.,Samuel Lunenfeld Research Institute |
Durocher D.,University of Toronto
Genes and Development | Year: 2010
DNA double-strand breaks (DSBs) are a threat to cell survival and genome integrity. In addition to canonical DNA repair systems, DSBs can be converted to telomeres by telomerase. This process, herein termed telomere healing, endangers genome stability, since it usually results in chromosome arm loss. Therefore, cells possess mechanisms that prevent the untimely action of telomerase on DSBs. Here we report that Mec1, the ATR ortholog, couples the detection of DNA ends with the inhibition of telomerase. Mec1 inhibits telomere healing by phosphorylating Cdc13 on its S306 residue, a phosphorylation event that suppresses Cdc13 accumulation at DSBs. Conversely, telomere addition at accidental breaks is promoted by Pph3, the yeast protein phosphatase 4 (PP4). Pph3 is itself modulated by Rrd1, an activator of PP2A family phosphatases. Rrd1 and Pph3 oppose Cdc13 S306 phosphorylation and are necessary for the efficient accumulation of Cdc13 at DNA breaks. These studies therefore identify a mechanism by which the ATR family of kinases enforces genome integrity, and a process that underscores the contribution of Cdc13 to the fate of DNA ends. © 2010 by Cold Spring Harbor Laboratory Press.
Boscher C.,University of British Columbia |
Dennis J.W.,Samuel Lunenfeld Research Institute |
Nabi I.R.,University of British Columbia
Current Opinion in Cell Biology | Year: 2011
Glycosylation is a common posttranslational modification of proteins and lipids of the secretory pathway that generates binding sites for galactose-specific lectins or galectins. Branching of Asn-linked (N-)glycans by the N-acetylglucosaminyltransferases (Mgat genes) increases affinity for galectins. Both tissue-specific expression of the enzymes and the metabolic supply of sugar-nucleotides to the ER and Golgi regulate glycan distribution while protein sequences specify NXS/T site multiplicity, providing metabolic and genetic contributions to galectin-glycoprotein interactions. Galectins cross-link glycoproteins forming dynamic microdomains or lattices that regulate various mediators of cell adhesion, migration, proliferation, survival and differentiation. There are a similar number of galactose-specific galectins in C. elegans and humans, but expression of higher-affinity branched N-glycans are a more recent feature of vertebrate evolution. Galectins might be considered a reading code for repetition of the minimal units of binding [Gal(NAc)β1-3/4GlcNAc] and NXS/T site multiplicity in proteins. The rapidly evolving and structurally complex Golgi modifications to surface receptors are interpreted through affinity for the lattice, which regulates receptor levels as a function of the cellular environment, and thereby the probability of various cell fates. Many important questions remain concerning the regulation of the galectins, the glycan ligands and lattice interaction with other membrane domains and endocytic pathways. © 2011 Elsevier Ltd.
Drucker D.J.,Samuel Lunenfeld Research Institute
Diabetes | Year: 2013
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote β-cell proliferation and survival in rodents. DPP-4 inhibitors expand β-cell mass, reduce α-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin-based therapies sustain functional β-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on β-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined. © 2013 by the American Diabetes Association.
Goodwin P.J.,Samuel Lunenfeld Research Institute
Breast | Year: 2013
Obesity is becoming increasingly prevalent and it has been linked to poor breast cancer outcomes. Because obesity is associated with increased adipose tissue mass and aromatase activity [the target of aromatase inhibitors (AIs)], there is concern that these agents may be less effective in women who are overweight or obese. Four of the randomized trials of AIs vs. tamoxifen conducted in the adjuvant breast cancer setting (ATAC, BIG 1-98 and TEAM in the postmenopausal setting and ABCSG-12 in the premenopausal setting) have reported effects of body mass index (BMI) on the relative effectiveness of an AI vs. tamoxifen. Obesity was confirmed as an adverse prognostic factor in ATAC and BIG 1-98 but not the TEAM study; in ABSCG-12, obesity was associated with poor outcomes in the anastrozole arm only. In the three postmenopausal trials, the use of an AI vs. tamoxifen was associated with better outcomes at all levels of BMI [all hazard ratios for recurrence <1, although 95% confidence intervals often included 1 due to lower power and smaller reductions in risk]. Of note, there was no significant interaction of BMI with letrozole (vs. tamoxifen) in the BIG 1-98 trial; while ATAC investigators concluded that the relative benefit of anastrozole (vs. tamoxifen) might be better in thinner (vs. heavier) women. In ABCSG-12, the use of anastrozole (vs. tamoxifen) was associated with significantly worse outcomes in women with BMI ≥25kg/m2 (similar to the detrimental effect of anastrozole on overall survival seen in the parent trial). These findings do not support the use of BMI as a predictor of AI (vs. tamoxifen) benefit in the adjuvant setting in postmenopausal breast cancer. © 2013 Elsevier Ltd.
McNeill H.,Samuel Lunenfeld Research Institute |
Woodgett J.R.,Samuel Lunenfeld Research Institute
Nature Reviews Molecular Cell Biology | Year: 2010
Signal transduction pathways interact at various levels to define tissue morphology, size and differentiation during development. Understanding the mechanisms by which these pathways collude has been greatly enhanced by recent insights into how shared components are independently regulated and how the activity of one system is contextualized by others. Traditionally, it has been assumed that the components of signalling pathways show pathway fidelity and act with a high degree of autonomy. However, as illustrated by the Wnt and Hippo pathways, there is increasing evidence that components are often shared between multiple pathways and other components talk to each other through multiple mechanisms. © 2010 Macmillan Publishers Limited. All rights reserved.
Ussher J.R.,Samuel Lunenfeld Research Institute |
Drucker D.J.,Samuel Lunenfeld Research Institute
Endocrine Reviews | Year: 2012
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that enhances glucose-stimulated insulin secretion and exerts direct and indirect actions on the cardiovascular system. GLP-1 and its related incretin hormone, glucose-dependent insulinotropic polypeptide, are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4), a key determinant of incretin bioactivity. Two classes of medications that enhance incretin action, GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors, are used for the treatment of type 2 diabetes mellitus. We review herein the cardiovascular biology of GLP-1R agonists and DPP-4 inhibitors, including direct and indirect effects on cardiomyocytes, blood vessels, adipocytes, the control of blood pressure, and postprandial lipoprotein secretion. Both GLP-1R activation and DPP-4 inhibition exert multiple cardioprotective actions in preclinical models of cardiovascular dysfunction, and short-term studies in human subjects appear to demonstrate modest yet beneficial actions on cardiac function in subjects with ischemic heart disease. Incretin-based agents control body weight, improve glycemic control with a low risk of hypoglycemia, decrease blood pressure, inhibit the secretion of intestinal chylomicrons, and reduce inflammation in preclinical studies. Nevertheless, there is limited information on the cardiovascular actions of these agents in patients with diabetes and established cardiovascular disease. Hence, a more complete understanding of the cardiovascular risk to benefit ratio of incretin-based therapies will require completion of long-term cardiovascular outcome studies currently underway in patients with type 2 diabetes mellitus. © 2012 by The Endocrine Society.
Al-Hakim A.K.,Samuel Lunenfeld Research Institute
Molecular & cellular proteomics : MCP | Year: 2012
Centrosomes are composed of a centriole pair surrounded by an intricate proteinaceous matrix referred to as pericentriolar material. Although the mechanisms underpinning the control of centriole duplication are now well understood, we know relatively little about the control of centrosome size and shape. Here we used interaction proteomics to identify the E3 ligase HERC2 and the neuralized homologue NEURL4 as novel interaction partners of the centrosomal protein CP110. Using high resolution imaging, we find that HERC2 and NEURL4 localize to the centrosome and that interfering with their function alters centrosome morphology through the appearance of aberrant filamentous structures that stain for a subset of pericentriolar material proteins including pericentrin and CEP135. Using an RNA interference-resistant transgene approach in combination with structure-function analyses, we show that the association between CP110 and HERC2 depends on nonoverlapping regions of NEURL4. Whereas CP110 binding to NEURL4 is dispensable for the regulation of pericentriolar material architecture, its association with HERC2 is required to maintain normal centrosome integrity. NEURL4 is a substrate of HERC2, and together these results indicate that the NEURL4-HERC2 complex participates in the ubiquitin-dependent regulation of centrosome architecture.
Logan A.G.,Samuel Lunenfeld Research Institute
Canadian Journal of Cardiology | Year: 2013
Achieving and sustaining good blood pressure control continues to be a challenge for many reasons including nonadherence with prescribed treatment and lifestyle measures, shortage of primary care physicians especially in less populated areas, and variations in physicians' practice behaviour. Many strategies have been advocated to improve outcomes with the greatest success being achieved using nurse or pharmacist-led interventions in which they were given the authority to prescribe or alter antihypertensive treatment. However, this treatment approach, which historically involved 1-on-1 visits to a doctor's office or pharmacy, proved costly, was not scalable, and did not actively engage patients in treatment decision-making. Several electronic health interventions have been designed to overcome these limitations. Though more patient-centred and often effective, they required wired connections and a personal computer, and logging on for Internet access and navigating computer screens greatly reduced access for many older patients. Furthermore, it is unclear whether the benefits were related to better case management or technological advances. Mobile health (mHealth) technology circumvents the technical challenges of electronic health systems and provides a more flexible platform to enhance patient self-care. mHealth applications are particularly appropriate for interventions that depend on patients' sustained adherence to monitoring schedules and prescribed treatments. Studies from our group in hypertension and other chronic conditions have shown improved health outcomes using mHealth applications that have undergone rigourous usability testing. Nonetheless, the inability of most electronic medical record systems to receive and process information from mobile devices continues to be a major impediment in realizing the full potential of mHealth technology. © 2013 Canadian Cardiovascular Society.
McNeill H.,Samuel Lunenfeld Research Institute
Cold Spring Harbor perspectives in biology | Year: 2010
The fur on a cat's back, the scales on a fish, or the bristles on a fly are all beautifully organized, with a high degree of polarization in their surface organization. Great progress has been made in understanding how individual cell polarity is established, but our understanding of how cells coordinate their polarity in forming coherent tissues is still fragmentary. The organization of cells in the plane of the epithelium is known as planar cell polarity (PCP), and studies in the past decade have delineated a genetic pathway for the control of PCP. This review will first briefly review data from the Drosophila field, where PCP was first identified and genetically characterized, and then explore how vertebrate tissues become polarized during development.