| 1. |
- Dahl, Markus
(författare)
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Mechanisms for Quantitative Regulation of TGF-ß Signaling
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Vanlandewijck, Michael, 1982-
(författare)
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Diversification of TGF-β Signaling in Homeostasis and Disease
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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