Conway Institute for Biomolecular and Biomedical Research
Department of Pharmacology
University College Dublin
Belfield Dublin 4 Ireland
Abstract
Since its discovery in 1979, p53 has become one of the most intensively studied genes of all time (over 15,000 articles published so far). However, some issues concerning p53 biology remained unresolved. What is in no doubt is the important role that p53 plays in regulating the response of cells to adverse stresses such as DNA damage. Indeed, this control mechanism is lost in over 50% of human cancers due to mutation of the p53 gene. A large number of therapies have been devised with p53 in mind, ranging from genetic therapies to more conventional drugs. Crucially, it is still controversial as to whether p53 mutants (i.e. the dysfunctional proteins produced upon mutation of the p53 gene) have additional tumour-promoting (oncogenic) properties that are independent of wild-type p53 inhibition. Our work has provided further evidence that mutant p53 proteins do portray such gain of function activities. We have identified a novel protein that interacts in both a physical and functional manner with certain mutant forms of the p53 protein. This protein was assigned the term MBP1 -for Mutant p53 Binding Protein 1. MBP1 is the fourth member of the emerging fibulin family. It displays both mutant p53-dependent and independent oncogenic properties. As such, MBP1 may be useful as a target for cancer therapy, along with being informative in terms of determining patient prognosis.