Indefinite. Restriction lift date: 10000-01-01
A study of translation regulation in cancer by application of ribosome profiling
University College Cork
Cancer is the name given to diverse diseases, whose common characteristic is uncontrolled cell proliferation. In an effort to rationalise the complexity of cancer Hanahan and Weinberg (2000, 2011) proposed the hallmarks that comprise biological capabilities that enable tumour development. Dysregulation of molecular pathways underlie these hallmarks of tumour progression and their study has been central to cancer biology. The PI3K/AKT/mTOR pathway has a central role in translation, cell growth and proliferation and it is frequently dysregulated in various cancers. In this work we aimed to elucidate the role of the PI3K pathway and protein synthesis in cancer. Our work focused on various levels of the PI3K pathway and protein synthesis, with application of ribosome profiling; a powerful technique, which provides genome-wide information on protein synthesis, by capturing actively translating ribosomes and sequencing of their associated transcripts. Previous work on bioinformatics and ribosome profiling data suggested the presence of an N-terminal extension in the well-studied tumour suppressor PTEN. Mutational analysis and further investigation of the 5’ leader of this gene performed in this study led to the discovery of previously uncharacterized proteoforms with N-terminal extensions. Given the physiological importance of PTEN this discovery is expected to broaden our understanding of the translational regulation of this gene and elucidate its role in molecular pathology. Polyamines are ubiquitous small basic molecules with known but not well defined roles in a range of physiological processes, including translation. The enzymes involved in this pathway are themselves subject to extensive translational regulation. In an effort to further characterize regulation of polyamines and their effect on translation we applied ribosome profiling in a previously established system available in the lab. This work confirmed our previous knowledge on regulation of enzymes of the polyamine pathway and identified previously uncharacterized translational events. Translation has a central role in physiology and its aberrations can cause cancer. Merkel Cell Carcinoma is a rare but aggressive tumour with poor prognosis and increasing incident rates. Approximately 80% of these cancers are induced by the Merkel Cell Polyomavirus (MCV). The small T (sT) viral antigen had been proposed to have a causal role in tumour initiation by affecting cap dependent translation. To study this molecular interaction we aimed to develop a model system that inducibly expresses MCV sT to imitate the initial steps of tumourigenesis and applied ribosome profiling on metastatic cell lines.
Ribosome profiling , Cancer , PTEN , PTEN-L , Merkel cell carcinoma , MCC , Merkel cell polyomavirus , MCV , MCPyV , Polyamines , Translation initiation
Tzani, I. 2016. A study of translation regulation in cancer by application of ribosome profiling. PhD Thesis, University College Cork.