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Diversification of ...
Diversification of TGF-β Signaling in Homeostasis and Disease
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- Vanlandewijck, Michael, 1982- (author)
- Uppsala universitet,Ludwiginstitutet för cancerforskning,TGF-ß signaling group
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- Moustakas, Aristidis, PhD (thesis advisor)
- Uppsala universitet,Ludwiginstitutet för cancerforskning
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- Heldin, Carl-Henrik, Professor (thesis advisor)
- Uppsala universitet,Ludwiginstitutet för cancerforskning
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- Dooley, Steven, Professor (opponent)
- Dept. of Medicine II, Medical Faculty Mannheim
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(creator_code:org_t)
- ISBN 9789155480981
- Uppsala : Acta Universitatis Upsaliensis, 2011
- English 77 s.
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Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 679
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Abstract
Subject headings
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- With the dawn of metazoans, the ability of cells to communicate with each other became of paramount importance in maintaining tissue homeostasis. The transforming growth factor β (TGF-β) signaling pathway, which plays important roles during embryogenesis and in the adult organism, signals via a heterodimeric receptor complex consisting of two type II and two type I receptors. After receptor activation through ligand binding, Smads mediate the signal from the receptor complex to the nucleus, where they orchestrate transcription. Depending on the context of activation, TGF-β can mediate a plethora of cellular responses, including proliferation, growth arrest, apoptosis and differentiation. In cancer, TGF-β can act as both as a tumor suppressor and promoter. During early stages of tumorigenesis, TGF-β prevents proliferation. However, TGF-β is also known to promote tumor progression during later stages of the disease, where it can induce differentiation of cancer cells towards a migratory phenotype. The aim of this thesis was to investigate how cells can differentiate their response upon TGF-β pathway activation. The first paper describes the role of Notch signaling in TGF-β induced growth arrest, demonstrating that TGF-β promotes Notch activity and that Notch signaling is required for prolonged TGF-β induced cell cycle arrest. In the second and third paper, we investigate the role of SIK, a member of the AMPK family of kinases, mediating signaling strength of TGF-β through degradation of the TGF-β type I receptor ALK5. While the second paper focuses on the effect of SIK on ALK5 stability and subsequent alterations in TGF-β signaling, the third paper emphasizes cooperation between SIK, Smad7 and the E3 ligase Smurf in degradation of ALK5. Finally, the fourth paper explores a novel role of SIK during TGF-β induced epithelial to mesenchymal transition (EMT). SIK binds to and degrades the polarity protein Par3, leading to enhanced EMT.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- TGF-β
- signaling
- SIK
- EMT
- polarity
- Notch
- ALK5
- p21
- growth arrest
- Smurf
- Smad7
- receptor
- SNF1LK
- Molecular biology
- Molekylärbiologi
- Biology with specialization in Molecular Cell Biology
- Biologi med inriktning mot molekylär cellbiologi
Publication and Content Type
- vet (subject category)
- dok (subject category)
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