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Intercellular variation in signaling through the TGF-β pathway and its relation to cell densityand cell cycle phase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. (Ola Söderberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2012 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, no 7, M111.013482Article in journal (Refereed) Published
Abstract [en]

Fundamental open questions in signal transduction remain concerning the sequence and distribution of molecular signaling events among individual cells. In this work we have characterized the intercellular variability of transforming growth factor β-induced Smad interactions, providing essential information about TGF-β signaling and its dependence on the density of cell populations and the cell-cycle phase. By employing the recently developed in situ proximity ligation assay, we investigated the dynamics of interactions and modifications of Smad proteins and their partners under native and physiological conditions. We analyzed the kinetics of assembly of Smad complexes and the influence of cellular environment and relation to mitosis. We report rapid kinetics of formation of Smad complexes, including native Smad2-Smad3-Smad4 trimeric complexes, in a manner influenced by the rate of proteasomal degradation of these proteins, and we found a striking cell to cell variation of signaling complexes. The single-cell analysis of TGF-β signaling in genetically unmodified cells revealed previously unknown aspects of regulation of this pathway, and it provided a basis for analysis of these signaling events to diagnose pathological perturbations in patient samples, and to evaluate their susceptibility to drug treatment.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2012. Vol. 11, no 7, M111.013482
National Category
Cell Biology
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-171949DOI: 10.1074/mcp.M111.013482ISI: 000306411300017PubMedID: 22442258OAI: oai:DiVA.org:uu-171949DiVA: diva2:512972
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Application of Proximity Ligation Assay for Multidirectional Studies on Transforming Growth Factor-β Pathway
Open this publication in new window or tab >>Application of Proximity Ligation Assay for Multidirectional Studies on Transforming Growth Factor-β Pathway
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A comprehensive understanding of how the body and all its components function is essential when this knowledge is exploited for medical purposes. The achievements in biological and medical research during last decades has provided us with the complete human genome and identified signaling pathways that governs the cellular processes that facilitates the development and maintenance of higher order organisms. This has brought about the realization that diseases such as cancer is a consequence of genomic aberrations that effects these signaling pathways, endowing cancer cells with the capacity to circumvent homeostasis by acquiring features like self-sustained proliferation and insensitivity to apoptosis. The increased understanding of biology and medicine has been made possible by the development of advanced methods to carry out biological and clinical analyses. The demands of a method often differ regarding in what context it will be applied. It may be acceptable for method to be laborious and time consuming if it is used in basic research, but for medical purposes molecular methods need to be fast and straightforward to perform. Innovative technologies should preferentially address the demands of both researchers and clinicians and provide data not possible to obtain by other methods. An example of such a method is the in situ proximity ligation assay (in situ PLA). In this thesis I have used this method to determine the activity status, at the single-cell level, of the transforming growth factor-β (TGF-β) signaling pathway and activating protein-1 (AP-1) family of transcription factors.  Both of these pathways are frequently involved in cancer development and progression. In addition to this research I herein also present further modifications of in situ PLA, and analyses thereof, to increase the utility and resolution of this assay.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 763
Keyword
proximity ligation, TGF-β signaling, Smad, single cell analysis, cell cycle, context-dependent signaling, CRC
National Category
Cell and Molecular Biology Cancer and Oncology Biomedical Laboratory Science/Technology
Research subject
Molecular Cellbiology; Medicinal Chemistry; Molecular Biology
Identifiers
urn:nbn:se:uu:diva-171952 (URN)978-91-554-8336-4 (ISBN)
Public defence
2012-05-25, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-02 Created: 2012-03-29 Last updated: 2013-09-02Bibliographically approved

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Publisher's full textPubMedhttp://www.mcponline.org/content/early/2012/03/22/mcp.M111.013482.full.pdf

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Zieba, AgataSöderberg, OlaMoustakas, AristidisHeldin, Carl-HenrikLandegren, Ulf

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