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Targeting the ubiquitin-proteasome system and ubiquitin-like protein conjugation pathways for non-genotoxic therapy of cancer

Objective

"The principal objective of our broad, translational research is to determine structural attributes and to develop small-molecule compounds for new, emerging, cancer-related protein-protein interactions in the ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways. We use nuclear magnetic resonance (NMR) and X-ray crystallography techniques to structurally characterize protein-protein interactions (PPI) and to develop small-molecule inhibitors for these PPIs. The UPS and UBL proteins studied by us are: the oncogenic E3 ligase Mdm2, which regulates levels of p53, the deubiquitinating enzyme (DUB) USP2a, and the UBL protein Hub1, which has been recently shown to control alternative splicing by non-covalent binding to the Snu66 spliceosomal protein. The E3 ligases and DUBs are considered to be the most important components of the ubiquitin conjugation system; this is because they directly bind to their target proteins and thus control substrate specificity. Hub1 connects the UBL pathway to the regulations of splice site usage and alternative splicing. Malfunctions in alternative splicing patterns are known to cause, among others, premature aging and cancer. The tumour suppressor p53 protein, ""the guardian of the genome"", has an overarching role in protecting the organism from cancer. In order to escape the safeguard system mediated by p53, nearly all human cancers have compromised the effectiveness of the p53 pathway. The restoration of the impaired function of the single gene, p53, by disrupting the Mdm2- p53/Mdmx-p53 interactions, offers a fundamentally new avenue for anticancer therapy across a broad spectrum of cancers."

Call for proposal

FP7-PEOPLE-2011-CIG
See other projects for this call

Coordinator

Jagiellonian University in Krakow
Address
Ul. Golebia 24
31007 Krakow
Poland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 100 000
Administrative Contact
Barbara Rys (Dr.)