Inactivation of the P53 gene plays an important role in cancer. One of the main functions of p53 protein is to elicit apoptosis in cells which have sustained genomic damage or that have undergone other | alterations which predispose them to become cancerous. There is an ample evidence that p53-mediates apoptosis is central to the function of p53 as a tumor suppressor in vivo. The mechanisms involved in the p53 mediated apoptosis are yet unknown, but p53 has recently been shown to transactivate the bax gene, whose product promotes apoptosis when present in excess. Furthermore, the wild type p53 protein can act also as a transcriptional repressor, and recent studies suggest a relationship between the p53-mediated transcriptional repression and apoptosis, opening a new way to better understanding the mechanisms involved in programmed cell death. The present project aims to determine the contribution of p53-mediate, transcriptional repression to apoptosis.
Among the main methodologies used will be: use of differential display to clone genes selectively repressed by p53 in cells wich undergo apoptosis; attempts to reverse apoptosis by upregulating the levels of p53-repressed genes, in transient transfection assays as well as through generation of stable cell lines with inducible expression.
It is espected that the findings will provide a better understanding of the molecular biology of p53-depende apoptosis. The impact in an area wich is the focus of much extensive research is espected to be real important. The present project also provides an excellent opportunity for high quality training in advance research methodologies.