Cancer is one of the most life-threatening diseases worldwide. Many anticancer treatments fail because they are not efficient or reveal too high side effects. Cancer cells develop due to unbalances... Show moreCancer is one of the most life-threatening diseases worldwide. Many anticancer treatments fail because they are not efficient or reveal too high side effects. Cancer cells develop due to unbalances in cell proliferation, cell cycle regulation and/or cell death. Identification of these aberrant molecular processes will reveal the essential processes leading to tumor formation and allows the generation of potential novel anticancer therapies. Interestingly, a group of viral and cellular proteins has been identified that harbors tumor-selective apoptosis activity. They are named Proteins Killing Tumor Cells (PKTCs). The aim of this thesis is to search for cellular processes sensed by the original PKTC, apoptin, which distinguish tumor cells from normal cells. Various tumor-related processes that are of importance for the tumor-selective activation of apoptin are reported. They range from proteasome activity and mitotic regulation to protein kinase and phosphatase action. The systematic analysis of both apoptin and other PKTCs reflects various differences between normal and tumor cells. Linking-up the various hallmarks of cancer with the aberrant processes sensed by apoptin and other PKTCs in cancer cells will hopefully contribute to a better understanding of tumor development as well as the generation of efficient and safe anticancer therapies. Show less
From the earliest times of their evolution, multi-cellular organisms have been defending themselves against infectious agents like nucleic acids, viruses, bacteria, fungi and parasites. Continuous... Show moreFrom the earliest times of their evolution, multi-cellular organisms have been defending themselves against infectious agents like nucleic acids, viruses, bacteria, fungi and parasites. Continuous selection pressure resulted in the development of sophisticated immune systems, which in their adaptive forms have exquisite specificity as well as memory for pathogen antigens. On the other hand, infectious agents developed elaborate strategies to escape from, or counteract, host defense mechanisms. Viruses are totally dependent upon host cells for replication and have developed an impressive variety of mechanisms to shield themselves from being detected by the host immune system. The subject of this thesis concerns a particular example of how viruses, specifically some members of genus Varicellovirus, counteract an important step in one of the acquired immunity pathways: the presentation of antigen by Major Histocompatibility Complex (MHC) class I molecules to cytotoxic T-cells. This thesis describes the discovery of a new family of proteins that inhibit the Transporter associated with Antigen Processing (TAP), and sets the first steps towards the explanation of how these inhibitors interfere with antigen transport by the MHC class I loading complex. Show less
