On the structure-function relationship of p73

Abstract: The development of multicellular organisms requires a balance between the cellular processes of proliferation, differentiation and death. These processes are important throughout the whole life of the organism. Daily, the DNA in our cells is under attack by agents that can cause damage. Thus, the cells have developed mechanisms to manage the DNA damage through activation of pathways leading to cell cycle arrest, DNA repair, and/or cell death. However, sometimes the damage affect the signaling pathways of cell cycle arrest, DNA repair and cell death, which then greatly enhances the risk of malignant transformation. Anticancer treatments aim to induce either cell cycle arrest or cell death, effects mediated by proteins such as p53 and p73. P53 is mutated in many tumors and consequently its role in the regulation of cell cycle and apoptosis is impaired. P73 is rarely mutated in human tumors. The P73 gene gives rise to many different protein isoforms, including transcriptionally active (TA) p73 isoforms and aminoterminal transactivation domain-deficient ΔN) isoforms. TAp73 isoforms are considered to act as tumor suppressors, whereas the ΔNp73 isoforms acts more like oncogenes, counteracting the functions of p53 and TAp73. Nevertheless, TAp73 isoforms are found to be overexpressed and to contribute to cellular chemoresistance in some tumors. On our way to explore the structure-function properties of p73 isoforms, we found that the full-length TAp73α isoform can prevent drug-induced apoptosis in small cell lung carcinoma cells and that this effect is in part mediated by Hsp72. In contrast, the pro-apoptotic actions of the shorter TAp73β isoform partially depend on the induction of p57Kip2. We characterized the domains within the p73 protein needed for its pro- or anti-apoptotic effect and also identified a novel transactivation domain in the carboxy-terminal region of p73. This transactivation domain was found to be regulated by PKC-dependent phosphorylation and active on promoters of cell cycle regulatory genes. In conclusion, these studies provide a better understanding of the structurefunction properties of p73 and how different domains selectively affect and regulate cell cycle progression and apoptosis. Elucidating the structure-function properties of p73 could lead to a better knowledge about how to manipulate the different actions of p73, which in turn could lead to the development of better and more efficient cancer treatments.