p73 : regulator of differentiation and apoptotic cell death

Neoplasia is characterized by cells' loss of self-control due to deregulated apoptotic and cell proliferation pathways. Anticancer treatments aim to induce either cell cycle arrest or apoptosis, and these effects are in most part mediated by proteins, like p53 and p73, which are involved in and able to mediate both processes. P53 is the gene found most mutated in tumors and consequently its pivotal role in the regulation of cell cycle and apoptosis is impaired.

The P53 homologue P73, on the other hand, is .rarely mutated in human tumors The P73 gene gives rise to many different protein isoforms, including the transcriptionally active p73 isoforms (TAp73) and the deltaNp73 isoforms, the latter lacking the amino-terminal transactivation (TA) domain. TAp73 isoforms are regarded most similar to p53 and to act as tumor suppressors, whereas the deltaNp73 isoforms acts more like oncogenes, preventing p53 and TAp73 from exerting their functions. Nevertheless, TAp73 isoforms are found overexpressed and to, contribute to cellular chemoresistance in some tumors. We have shown that the TAp73alpha isoform can prevent drug-induced apoptosis in small cell lung carcinoma cells and that this effect is exerted upstream of the mitochondria. In addition, we have characterized the domains within the protein needed for the pro- or anti-apoptotic effect of p73. Furthermore, in the carboxy-terminal region of p73 we characterized a TA domain containing a putative PKC phosporylation site. The characterized TA domain was active on promoters of cell cycle regulatory genes, and its activity was found to be regulated by phosphorylation.

In conclusion, these studies provide a better understanding into the structure-function properties of p73 and how different domains can selectively affect and regulate cell cycle progression and/or apoptosis.

List of scientific papers

I. Nyman U, Sobczak-Pluta A, Vlachos P, Perlmann T, Zhivotovsky B, Joseph B (2005). "Full-length p73alpha represses drug-induced apoptosis in small cell lung carcinoma cells." J Biol Chem 280(40): 34159-69. Epub 2005 Aug 8
https://pubmed.ncbi.nlm.nih.gov/16087678

II. Nyman U, Zhivotovsky B, Joseph B (2007). "PKC-dependent phosphorylation regulates the cell cycle inhibitory function of the p73 carboxy-terminus transactivation domain." (Submitted)