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The physiological role of E2F1 acetylation: a gene targeting approach

Final Activity Report Summary - AKME (The physiological role of E2F1 acetylation: a gene targeting approach)

PRB is one of the most important tumour suppressive proteins which, since its discovery, has been a focal point of cancer research. At a molecular level, pRB exerts its functions through the interaction with the E2F1 protein. The resulting pRB-E2F1 protein complex regulates the expression of genes relevant to cellular growth and cell death. Alterations of pRB-E2F1 activity have been implicated in a wide variety of tumours.

Dr Ianari applied a combination of in vitro, i.e. cellular-based, and in vivo, i.e. mouse-based, approaches to study the mechanisms that regulated the function of the pRB-E2F1 complex in response to deoxyribonucleic acid (DNA) damaging insults, such as chemotherapeutic agents and ionising radiations. The results of these studies indicated that pRB could arrest cellular proliferation or promote cell death in response to genotoxic stress, through the regulation of E2F1 activity. The studies also suggested that a modification of pRB and E2F1, named acetylation, was important to regulate the formation of the pRB-E2F1 complex and therefore its tumour suppressive activities in the DNA damage response. Based on these results Dr Ianari decided to expand her studies through the generation of two mouse models to allow for the re-expression of the pRB or the E2F1 mutant proteins. These models would allow the unequivocal in vivo validation of the role of the pRB-E2F1 complex acetylation during tumourigenesis as well as in the response and resistance to chemotherapeutic drugs, thus facilitating the design of new therapeutic tools.