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Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. 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 and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 31, 3606-3615 p.Article in journal (Refereed) Published
Abstract [en]

Deregulation of the transforming growth factor β (TGFβ) signal transduction cascade is functionally linked to cancer. In early phases, TGFβ acts as a tumor suppressor by inhibiting tumor cell proliferation, whereas in late phases, it can act as a tumor promoter by stimulating tumor cell invasion and metastasis. Smad transcriptional effectors mediate TGFβ responses, but relatively little is known about the Smad-containing complexes that are important for epithelial-mesenchymal transition and invasion. In this study, we have tested the hypothesis that specific members of the AP-1 transcription factor family determine TGFβ signaling specificity in breast cancer cell invasion. Using a 3D model of collagen-embedded spheroids of MCF10A-MII premalignant human breast cancer cells, we identified the AP-1 transcription factor components c-Jun, JunB, c-Fos and Fra1 as essential factors for TGFβ-induced invasion and found that various mesenchymal and invasion-associated TGFβ-induced genes are co-regulated by these proteins. In situ proximity ligation assays showed that TGFβ signaling not only induces complexes between Smad3 and Smad4 in the nucleus but also complexes between Smad2/3 and Fra1, whereas complexes between Smad3, c-Jun and JunB could already be detected before TGFβ stimulation. Finally, chromatin immunoprecipitations showed that c-Jun, JunB and Fra1, but not c-Fos, are required for TGFβ-induced binding of Smad2/3 to the mmp-10 and pai-1 promoters. Together these results suggest that in particular formation of Smad2/3-Fra1 complexes may reflect activation of the Smad/AP-1-dependent TGFβ-induced invasion program.

Place, publisher, year, edition, pages
2013. Vol. 32, no 31, 3606-3615 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-180124DOI: 10.1038/onc.2012.370ISI: 000322638400005PubMedID: 22926518OAI: oai:DiVA.org:uu-180124DiVA: diva2:548236
Note

Agata Zieba & Eleftheria Vasilaki contributed equally to this work.

Available from: 2012-08-30 Created: 2012-08-30 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)
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Available from: 2012-05-02 Created: 2012-03-29 Last updated: 2013-09-02Bibliographically approved

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Sundqvist, AndersZieba, AgataVasilaki, EleftheriaHerrera Hidalgo, CarmenSöderberg, OlaMiyazono, KoheiHeldin, Carl-HenrikLandegren, Ulften Dijke, Peter

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Sundqvist, AndersZieba, AgataVasilaki, EleftheriaHerrera Hidalgo, CarmenSöderberg, OlaMiyazono, KoheiHeldin, Carl-HenrikLandegren, Ulften Dijke, Peter
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