| dc.description.abstract | The pivotal role of the transcription factor p53 in tumor suppression remains unchallenged; however, the role of its family member, p73, in normal cellular function and tumorigenesis is far from certain. The goal of this dissertation is to better understand the mechanisms that regulate p73 function as well as develop significant insight into the biological systems that p73 controls through its transcriptional activity. To elucidate these goals we investigated biological systems in which p73 activity is essential as well as identified putative protein-protein interactions that regulate p73.
¬¬¬ In this dissertation, we discovered that that p73 is a necessary transcriptional regulator of the process of ciliary biogenesis within multiciliated cells (MCCs). Loss of MCCs provided a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus, hippocampal dysgenesis, sterility and chronic inflammation/infection of lung, middle ear and sinus. We found p73 is expressed in MCCs as well as co-expressed with p63 in a subset of basal, tracheal epithelial cells, suggesting that p73 ‘marks’ these cells for MCC differentiation. Furthermore, through in situ p63/p73 ChIP-seq of the murine trachea, we identified genomic binding sites in proximity to genes that regulate MCC differentiation, from cell cycle arrest (Cdkn1a) and amplification of centrioles (Myb) to apical docking of centrioles with components that make up the axoneme [Foxj1 and Traf3ip1]. By combining our ChIP-seq data with RNA-seq of tracheal epithelial cells, we found evidence for p73-dependent, direct and indirect transcriptional regulation of a broad network of cilia-associated genes. In sum, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation and, like p63, has an essential role in development of tissues. Research results presented in this dissertation are not only significant value to the understanding of p73 but also to the understanding of MCC differentiation. This work lays essential groundwork for future studies investigating roles and regulation of p73 within the correct biological contexts. | |
