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Functional analysis of novel interactors of mammalian p53 and p53-related proteins
Di Minin, Giulio
2012-04-24
Abstract
The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of stress, primarily by inducing cell cycle arrest or apoptosis. Mutation of p53, which is one of the most frequent genetic alterations detected in human cancers, inactivates these growth regulatory functions; in addition, very often mutant p53 acquires tumor-promoting activities (gain-of-function). A complete and thorough understanding of the signaling circuitry that regulates wild-type and mutant p53 functions is therefore a primary objective for basic cancer research, since it may lead to development of important tools for diagnosis and therapy of tumors. One crucial component of such knowledge is the protein interaction profile of p53.
To gain novel insights on p53 interactions, we used a phylogenetic approach. We reasoned that a comprehensive map of the protein interaction profile of Drosophila p53 might reveal conserved interactions of the entire p53 family in man. Using a genome-scale in vitro expression cloning approach, we identified 91 previously unreported Dmp53 interactors. Next, we studied and characterized the interaction of human orthologs of newly identified Dmp53 interactors with all p53-family proteins, and it resulted in the identification of several novel interactants of this family of tumor suppressors (Part 1 of this Thesis).
In parallel, we verified that many of the mammalian orthologs of Dmp53 interactors could also bind to an oncogenic p53 mutant (R175H), and therefore are potential novel targets or effectors of mut-53 gain of function activities. Among those proteins we focused our attention on DAB2IP, a tumor-suppressor gene that functions by counteracting the activation of multiple oncogenic pathways. There are evidences that mutant p53 has a stimulatory role in all the signaling pathways that are normally inhibited by DAB2IP; therefore, we propose that mutant p53 may bind and functionally inactivate DAB2IP as one of the mechanisms of its gain-of-function. Given the crucial role of DAB2IP in modulating cellular responses to TNF, we focus on the potential relevance of this interaction in the connection between inflammation and cancer (Part 2 of this Thesis).
Insegnamento
Publisher
Università degli studi di Trieste
Languages
en
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