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Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany.
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA.
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2011 (English)In: Molecular Systems Biology, ISSN 1744-4292, Vol. 7, no 492Article in journal (Refereed) Published
Abstract [en]

Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF-beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination.

Place, publisher, year, edition, pages
EMBO and Macmillan Publishers Limited , 2011. Vol. 7, no 492
Keyword [en]
mathematical model, Smad, TGF-beta, ultrasensitivity
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-155228DOI: 10.1038/msb.2011.22ISI: 000291351000003OAI: oai:DiVA.org:uu-155228DiVA: diva2:425509
Available from: 2011-06-21 Created: 2011-06-20 Last updated: 2012-08-01Bibliographically approved
In thesis
1. Mechanisms for Quantitative Regulation of TGF-ß Signaling
Open this publication in new window or tab >>Mechanisms for Quantitative Regulation of TGF-ß Signaling
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is a widely spread disease, and many cancer variants are today still difficult to treat. Efforts are being made to understand the complexity of cancer, both at a clinical level but also at a pre-clinical level. The aim is of course to merge the research from both disciplines, as an example, find out how to treat a tumour in a patient and what molecular mechanisms are behind the origin of the tumour. Basic research provides a platform that in the long run will help to create treatments for many cancer variants that exist today. Transforming Growth Factor Beta (TGF-ß) is a cytokine that regulates many cellular events such as cell differentiation, cell proliferation and migration. TGF-ß signaling is important to study since many studies show that patients with cancer actually have accumulated mutations in proteins connected to the pathway. In this thesis I try to enhance the knowledge of the TGF-ß signaling pathway, looking in more detail how the signaling output is regulated by the response to the ligand, explained in paper four. Furthermore I try to reveal the protein network that control transmission of the signal from the cell surface to the nucleus. We found that PARP-1 (paper one and two) and PARP-2 (paper three) associates with the signaling pathway to regulate the Smad proteins and to negatively regulate the transcription of Smad target genes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 41 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 767
National Category
Natural Sciences Cell Biology
Research subject
Biology with specialization in Molecular Cell Biology
urn:nbn:se:uu:diva-172855 (URN)978-91-554-8351-7 (ISBN)
Public defence
2012-06-07, B42, Biomedical Center (BMC), Husargatan 3, C11, Uppsala, 09:00 (English)
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved

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