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Mechanisms for Quantitative Regulation of TGF-ß Signaling
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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.
Series
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
Identifiers
URN: urn:nbn:se:uu:diva-172855ISBN: 978-91-554-8351-7 (print)OAI: oai:DiVA.org:uu-172855DiVA: diva2:515852
Public defence
2012-06-07, B42, Biomedical Center (BMC), Husargatan 3, C11, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved
List of papers
1. PARP-1 attenuates Smad-mediated transcription
Open this publication in new window or tab >>PARP-1 attenuates Smad-mediated transcription
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2010 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 40, no 4, 521-532 p.Article in journal (Refereed) Published
Abstract [en]

The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-128847 (URN)10.1016/j.molcel.2010.10.029 (DOI)000284988400006 ()21095583 (PubMedID)
Available from: 2010-07-28 Created: 2010-07-27 Last updated: 2017-12-12Bibliographically approved
2. Regulation of novel gene targets of TGFβ signaling by PARP-1
Open this publication in new window or tab >>Regulation of novel gene targets of TGFβ signaling by PARP-1
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences Cell Biology
Identifiers
urn:nbn:se:uu:diva-172851 (URN)
Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2012-08-01
3. PARP-2 activation and association with Smads during regulation of TGFβ signaling
Open this publication in new window or tab >>PARP-2 activation and association with Smads during regulation of TGFβ signaling
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(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences Cell Biology
Identifiers
urn:nbn:se:uu:diva-172853 (URN)
Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2012-08-01
4. Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
Open this publication in new window or tab >>Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
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2011 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-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
Keyword
mathematical model, Smad, TGF-beta, ultrasensitivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-155228 (URN)10.1038/msb.2011.22 (DOI)000291351000003 ()
Available from: 2011-06-21 Created: 2011-06-20 Last updated: 2017-12-11Bibliographically approved

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