Laboratory of Systems Biology
Laboratory of Systems Biology
Sasi N.K.,Van Andel Research Institute |
Sasi N.K.,Laboratory of Systems Biology |
Sasi N.K.,Michigan State University |
Bhutkar A.,Massachusetts Institute of Technology |
And 3 more authors.
Neoplasia (United States) | Year: 2017
DBF4-dependent kinase (DDK) is a two-subunit kinase required for initiating DNA replication at individual origins and is composed of CDC7 kinase and its regulatory subunit DBF4. Both subunits are highly expressed in many diverse tumor cell lines and primary tumors, and this is correlated with poor prognosis. Inhibiting DDK causes apoptosis of tumor cells, but not normal cells, through a largely unknown mechanism. Firstly, to understand why DDK is often overexpressed in tumors, we identified gene expression signatures that correlate with DDK high- and DDK low-expressing lung adenocarcinomas. We found that increased DDK expression is highly correlated with inactivation of RB1-E2F and p53 tumor suppressor pathways. Both CDC7 and DBF4 promoters bind E2F, suggesting that increased E2F activity in RB1 mutant cancers promotes increased DDK expression. Surprisingly, increased DDK expression levels are also correlated with both increased chemoresistance and genome-wide mutation frequencies. Our data further suggest that high DDK levels directly promote elevated mutation frequencies. Secondly, we performed an RNAi screen to investigate how DDK inhibition causes apoptosis of tumor cells. We identified 23 kinases and phosphatases required for apoptosis when DDK is inhibited. These hits include checkpoint genes, G2/M cell cycle regulators, and known tumor suppressors leading to the hypothesis that inhibiting mitotic progression can protect against DDKi-induced apoptosis. Characterization of one novel hit, the LATS2 tumor suppressor, suggests that it promotes apoptosis independently of the upstream MST1/2 kinases in the Hippo signaling pathway. © 2017
Gemayel R.,Laboratory of Systems Biology |
Chavali S.,University of Cambridge |
Pougach K.,Laboratory of Systems Biology |
Legendre M.,Aix - Marseille University |
And 9 more authors.
Molecular Cell | Year: 2015
Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions. © 2015 The Authors.
News Article | November 15, 2016
Different cells of the human body differ greatly in structure and function. However, variation exists even among cells of one type. New research from investigators at the National Institutes of Health suggests the magnitude of such differences in T lymphocytes, or T cells, may indicate an individual's age and genetic predisposition to disease. Learning more about so-called cell-to-cell expression variation, or CEV, may further illuminate how the immune system functions and one day serve as a diagnostic tool to help implement personalized medicine, according to the researchers. The scientists, led by John S. Tsang, Ph.D., of the Laboratory of Systems Biology at the National Institute of Allergy and Infectious Diseases, part of NIH, published their findings today in the journal Immunity. In this first-in-human analysis, Dr. Tsang, computational biologist Yong Lu, Ph.D., and their colleagues used data from a previous study in which blood samples from a healthy, unrelated cohort of individuals were drawn at an initial visit, one week later, and at two months. The scientists analyzed different subtypes of T cells--immune cells that facilitate, regulate and direct the destruction of infected or cancerous cells--in these samples by quantifying protein expression in single cells. While identifying cell-surface proteins is a standard method for categorizing T cells, the NIH team also quantified cell-to-cell variation of protein levels and compared how such differences varied among individuals and in a single person over time. Although the degree of cell-to-cell variation for many protein and cell combinations remained relatively constant in individuals over the two-month observation period, the magnitude of variation seemed to differ among individuals and could serve as unique personal markers, the authors write. Furthermore, certain variations were associated with age and carrying genes linked to disease. For example, individuals who carried a genetic variant associated with an increased risk for developing asthma were more likely to have more variable expression of a specific protein called CD38 among a subtype of T cells. The team plans to use the framework they developed to help identify potential CEV biomarkers for autoimmune diseases and other health problems. Learn more about this study and explore interactive figures portraying the study data. ARTICLE: Y Lu et al. Systematic Analysis of Cell-to-Cell Expression Variation of T Lymphocytes in a Human Cohort Identifies Aging and Genetic Associations. Immunity DOI: 10.1016/j.immuni.2016.10.025 (2016). WHO: Principal investigator John S. Tsang, Ph.D., Systems Genomics and Bioinformatics Unit Chief in the Laboratory of Systems Biology in NIAID's Division of Intramural Research, is available to comment. NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .
Furge K.A.,Laboratory of Computational Biology |
MacKeigan J.P.,Laboratory of Systems Biology |
Teh B.T.,Laboratory of Cancer Genetics |
Teh B.T.,National Cancer Center
The Lancet Oncology | Year: 2010
Renal-cell carcinoma is a heterogeneous group of tumours that arise in the adult kidneys. Irrespective of the type of renal tumour, traditional chemotherapeutic and radiation-based therapies have been largely ineffective at treating advanced tumours, with long-term survival being very low. Molecularly-targeted inhibitors of protein kinases are effective in delaying progression of advanced renal tumours. These therapies revolve around inhibition of the vascular endothelial growth factor receptor tyrosine kinase and the mammalian target of rapamycin serine or threonine kinase signalling pathways. The genetic complexity of renal tumours revealed by gene-expression profiling and other molecular-genetic technologies indicate that inhibition of additional kinase-associated pathways could also prevent renal tumour growth. In this review, we discuss the use of molecularly-targeted kinase inhibitors in the treatment of renal-cell carcinoma and identify the next generation of kinase inhibitors that show promise for treatment. © 2010 Elsevier Ltd.
Itoh S.,Stanford University |
Kimura N.,Stanford University |
Axtell R.C.,Stanford University |
Velotta J.B.,Stanford University |
And 18 more authors.
Circulation | Year: 2011
Background-Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice. Methods and Results-Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17) or-wild-type mice. Allograft survival was significantly prolonged in IL-17 recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17 recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17 recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4 and CD8 T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2 recipient mice engrafted with either wild-type or IL-17 CD4 and CD8 T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls. Conclusions-During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4 and CD8 T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection. © 2011 American Heart Association, Inc.
Aslankoohi E.,Laboratory of Systems Biology |
Aslankoohi E.,Catholic University of Leuven |
Rezaei M.N.,AMD Inc |
Vervoort Y.,Laboratory of Systems Biology |
And 4 more authors.
PLoS ONE | Year: 2015
Glycerol is the main compatible solute in yeast Saccharomyces cerevisiae. When faced with osmotic stress, for example during semi-solid state bread dough fermentation, yeast cells produce and accumulate glycerol in order to prevent dehydration by balancing the intracellular osmolarity with that of the environment. However, increased glycerol production also results in decreased CO2 production, which may reduce dough leavening. We investigated the effect of yeast glycerol production level on bread dough fermentation capacity of a commercial bakery strain and a laboratory strain. We find that Δgpd1 mutants that show decreased glycerol production show impaired dough fermentation. In contrast, overexpression of GPD1 in the laboratory strain results in increased fermentation rates in high-sugar dough and improved gas retention in the fermenting bread dough. Together, our results reveal the crucial role of glycerol production level by fermenting yeast cells in dough fermentation efficiency as well as gas retention in dough, thereby opening up new routes for the selection of improved commercial bakery yeasts. © 2015 Aslankoohi et al.