Mechanisms for Quantitative Regulation of TGF-ß Signaling

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.