Pacific Northwest Research Institute

Broadway, WA, United States

Pacific Northwest Research Institute

Broadway, WA, United States

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Hakomori S.-I.,Pacific Northwest Research Institute | Hakomori S.-I.,University of Washington
FEBS Letters | Year: 2010

Glycosphingolipids (GSLs) GM3 (NeuAcα3Galβ4Glcβ1Cer) and GM2 (GalNAcβ4[NeuAcα3]Galβ4Glcβ1Cer) inhibit (i) cell growth through inhibition of tyrosine kinase associated with growth factor receptor (GFR), (ii) cell adhesion/motility through inhibition of integrin-dependent signaling via Src kinases, or (iii) both cell growth and motility by blocking " cross-talk" between integrins and GFRs. These inhibitory effects are enhanced when GM3 or GM2 are in complex with specific tetraspanins (TSPs) (CD9, CD81, CD82). Processes (i)-(iii) occur through specific organization of GSLs with key molecules (TSPs, caveolins, GFRs, integrins) in the glycosynaptic microdomain. Some of these processes are shared with epithelial-mesenchymal transition induced by TGFβ or under hypoxia, particularly that associated with cancer progression. © 2009 Federation of European Biochemical Societies.


Hakomori S.-I.,Pacific Northwest Research Institute | Hakomori S.-I.,University of Washington | Handa K.,Pacific Northwest Research Institute
Glycoconjugate Journal | Year: 2015

Our studies during the early 1970s showed that expression of GM3, the simplest ganglioside and an abundant animal cell membrane component, is reduced during malignant transformation of cells by oncogenic viruses. Levels of mRNA for GM3 synthase were reduced in avian and mammalian cells transformed by oncoprotein "v-Jun", and overexpression of GM3 synthase in the transformed cells caused reversion from transformed to normal cell-like phenotype. GM3 has a well-documented inhibitory effect on activation of growth factor receptors (GFRs), particularly epidermal GFR (EGFR). De-N-acetyl GM3, which is expressed in some invasive human cancer cells, has an enhancing effect on EGFR activation. The important role of the sialosyl group of GM3 was demonstrated using NEU3, a plasma membrane-associated sialidase that selectively remove sialic acids from gangliosides GM3 and GD1a and is up-regulated in many human cancer cells. GM3 is highly enriched in a type of membrane microdomain termed "glycosynapse", and forms complexes with co-localized cell signaling molecules, including Src family kinases, certain tetraspanins (e.g., CD9, CD81, CD82), integrins, and GFRs (e.g., fibroblast growth factor receptor and hepatocyte growth factor receptor c-Met). Studies by our group and others indicate that GM3 modulates cell adhesion, growth, and motility by altering molecular organization in glycosynaptic microdomains and the activation levels of co-localized signaling molecules that are involved in cancer pathogenesis. © 2015 Springer Science+Business Media New York.


Schneider J.G.,Luxembourg Center for Systems Biomedicine | Schneider J.G.,Saarland University | Nadeau J.H.,Pacific Northwest Research Institute
Cell Metabolism | Year: 2015

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that peripheral serotonin controls thermogenesis in adipose tissue by modulating β-adrenergic stimulation of UCP-1, thereby affecting glucose homeostasis and weight gain. © 2015 Elsevier Inc.


Handa K.,Pacific Northwest Research Institute | Hakomori S.-I.,Pacific Northwest Research Institute | Hakomori S.-I.,University of Washington
Glycoconjugate Journal | Year: 2012

Two types of carbohydrate to carbohydrate interaction (CCI) have been known to be involved in biological processes. One is the CCI between molecules expressed on interfacing cell membranes of different cells to mediate cell to cell adhesion, and subsequently induce cell signaling, and is termed trans-CCI. It has been indicated that the Lex to Lex interaction at the morula stage in mouse embryos plays an important role in the compaction process in embryonic development. GM3 to Gg3 or GM3 to LacCer interaction has been suggested to be involved in adhesion of tumor cells to endothelial cells, which is considered a crucial step in tumor metastasis. The other is the CCI between molecules expressed within the same microdomain of the cell surface membrane, and is termed cis-CCI. The interaction between ganglioside GM3, and multi (>3) GlcNAc termini of N-linked glycans of epidermal growth factor receptor (EGFR), has been indicated as the molecular mechanism for the inhibitory effect of GM3 on EGFR activation. Also, the complex with GM3 and GM2 has been shown to inhibit the activation of hepatocyte growth factor (HGF) receptor, cMet, through its association with tetraspanin CD82, and results in the inhibition of cell motility. Since CCI research is still limited, more examples of CCI in biological processes in development, and cancer progression will be revealed in the future. © Springer Science+Business Media, LLC 2012.


Riordan J.D.,Pacific Northwest Research Institute | Nadeau J.H.,Pacific Northwest Research Institute
Mammalian Genome | Year: 2014

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world and its prevalence is rising. In the absence of disease progression, fatty liver poses minimal risk of detrimental health outcomes. However, advancement to non-alcoholic steatohepatitis (NASH) confers a markedly increased likelihood of developing severe liver pathologies, including fibrosis, cirrhosis, organ failure, and cancer. Although a substantial percentage of NAFLD patients develop NASH, the genetic and molecular mechanisms driving this progression are poorly understood, making it difficult to predict which patients will ultimately develop advanced liver disease. Deficiencies in mechanistic understanding preclude the identification of beneficial prognostic indicators and the development of effective therapies. Mouse models of progressive NAFLD serve as a complementary approach to the direct analysis of human patients. By providing an easily manipulated experimental system that can be rigorously controlled, they facilitate an improved understanding of disease development and progression. In this review, we discuss genetically- and chemically-induced models of NAFLD that progress to NASH, fibrosis, and liver cancer in the context of the major signaling pathways whose disruption has been implicated as a driving force for their development. Additionally, an overview of nutritional models of progressive NAFLD is provided. © 2014, The Author(s).


Patent
Pacific Northwest Research Institute | Date: 2010-05-17

The invention is directed to compositions and methods for the detection of a malignant condition, and relates to the discovery of soluble forms of mesothelin polypeptides, including mesothelin related antigen (MRA). In particular the invention provides a nucleic acid sequence encoding MRA and an MRA variant. The invention also provides a method of screening for the presence of a malignant condition in a subject by detecting reactivity of an antibody specific for a mesothelin polypeptide with a molecule naturally occurring in soluble form in a sample from such a subject, and by hybridization screening using an MRA nucleotide sequence, as well as other related advantages.


Patent
Pacific Northwest Research Institute | Date: 2011-05-18

The invention is directed to compositions and methods for the detection of a malignant condition, and relates to the discovery of soluble and cell surface forms of HE4a polypeptides, including HE4a that is overexpressed in ovarian carcinomas. In particular the invention provides a nucleic acid sequence encoding HE4a, and also provides a method of screening for the presence of a malignant condition in a subject by detecting reactivity of an antibody specific for a HE4a polypeptide with a molecule naturally occurring in soluble and/or cell surface form in a sample from such a subject, and by hybridization screening using an HE4a nucleotide sequence, as well as other related advantages.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 299.74K | Year: 2013

A living system is distinguished from most of its non-living counterparts by the way it stores and transmits information. It is just this biological information that is the key to the biological functions. It is also at the heart of the conceptual basis of what we call systems biology. Much of the conceptual structure of systems biology can be built around the fundamental ideas concerning the storage transmission and use of biological information. Biological information resides, of course, in digital sequences in molecules like DNA and RNA, but also in 3-dimensional structures, chemical modifications, chemical activities, both of small molecules and enzymes, and in other components and properties of biological systems at many levels. The information depends critically on how each unit interacts with, and is related to, other components of the system. Biological information is therefore inherently context-dependent, which raises significant issues concerning its quantitative measure and representation. An important and immediate issue for the effective theoretical treatment of biological systems then is: how can context-dependent information be usefully represented and measured? This is important both to the understanding of the storage and flow of information that occurs in the functioning of biological systems and in evolution. This work involves both new ideas and the integration of new ideas. It represents new mathematical methods as well as a novel integration of approaches that are focused on the very real and practical problems of biological data analysis. The PI as developed a new conceptual approach that is novel and mathematically well-defined, exploring the relationships between graph properties and set complexity and considering new approaches to network analysis. New interaction distance measures are considered with a new way of dealing with especially large data sets, especially the maximal information coefficient, for which a general approach may be possible, certainly for a small number of variables, and possibly in the general case. The ideas will be tested on a number of diverse biological data sets, especially around gene expressions, and other variants. Current methods often fail in the face of truly complex dependencies in large data sets, and powerful new methods would be of high value. This work involves both new ideas and the integration of new ideas. It represents new mathematical methods as well as a novel integration of approaches that are focused on the very real and practical problems of biological data analysis.


Patent
Pacific Northwest Research Institute | Date: 2015-07-27

The invention is directed to compositions and methods for the detection of a malignant condition, and relates to the discovery of soluble and cell surface forms of HE4a polypeptides, including HE4a that is overexpressed in ovarian carcinomas. In particular the invention provides a nucleic acid sequence encoding HE4a, and also provides a method of screening for the presence of a malignant condition in a subject by detecting reactivity of an antibody specific for a HE4a polypeptide with a molecule naturally occurring in soluble and/or cell surface form in a sample from such a subject, and by hybridization screening using an HE4a nucleotide sequence, as well as other related advantages.


Patent
Pacific Northwest Research Institute | Date: 2015-09-02

Provided are methods of screening for the presence of ovarian carcinoma in a subject. The methods involved contacting a blood, serum, or plasma sample from the subject with an antibody specific for the polypeptide of SEQ ID NO:11. This allows determination of the presence in the biological sample of a molecule that naturally occurs in soluble form, and has an antigenic determinant that is reactive with the antibody. This, in turn, allows detection of the presence of a malignant condition in the subject. The antibody may be a monoclonal antibody, such as a murine monoclonal antibody. Detection of the binding of the antibody to the antigenic determinant may be effected via spectrophotometric detection of a product of an enzyme reaction, for example via enzyme linked immunosorbent assay (ELISA). The subject may have an early stage of ovarian cancer.

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