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Project leader Volarevic Siniša
Project co-leader: Zlatko Dembic
Administering organization: School of Medicine University of Rijeka Brace Branchetta 20 51000 Rijeka Croatia
Partner Institution/Company: Department of Oral Biology, University of Oslo
Grant type: 1B
Project title: Regulation of the p53 tumor suppressor by ribosomal proteins in physiological and pathological conditions.
Project summary: The capacity of p53 protein to detect many cancer-related stresses and appropriately respond by regulating target genes that induce various biological responses is essential for prevention of malignancies in humans. Currently, it is not known how such diversity of stress signals can be integrated by a single molecule. The Volarević group has recently reported a seminal observation that genetic disruption of ribosome biogenesis by conditional deletion of one allele of ribosomal protein S6 gene elicits a p53-dependent checkpoint response. Based on the available literature other researchers proposed that most p53-inducing stresses compromise ribosome biogenesis and nucleolar structure. Furthermore, a few ribosomal proteins (RPS) have been suggested as transducers of p53-activating signals in response to pharmacologic inhibition of ribosome biogenesis. Taking into account these observations, we put forward the hypothesis that a number of cancer-related stresses utilize RPS to activate the p53 tumor suppressor and that a failure of this mechanism might lead to malignant transformation, tumor progression and resistance to anti-cancer therapies. To test this hypothesis, we propose the following specific aims: 1. To determine whether RPL5, RPL11, RPL23, RPL26 and RPS7 participate in p53 activation in response to deficiencies in RPS6 and RPL24 as well as a number of different cellular stresses. 2. To identify human colon cancer-associated mutations in the RPL11 gene by genomic DNA sequencing. 3. To test the functional significance of colon cancer-associated mutation in the RPL11 gene. This project is expected to yield a better and comprehensive understanding of the role of RPS in p53 activation by various stresses, as well as their role in colon cancer, the second leading cause of overall cancer mortality in Croatia. Addressing these issues will involve state-of-the-art methodology: genetic manipulations of RP genes, molecular and cellular biology techniques, immunological methods and sequencing of RP genomic DNAs in human colon cancer. The initiative brings together two high quality research groups with common scientific interests, yet with a different perspective. The strength of collaboration between Prof. Volarević’s and Prof. Dembić’s groups is based on complementary experience, expertise, specialized methods and tools available in each of the two laboratories. The project should positively impact the research capacity, education and science in Croatia via scientific cooperation of Croatian researchers with Croatian scientific Diaspora. Moreover, it is expected to lead, in the future, to the development of improved therapies and/or intellectual property that could result in a significant financial benefit for Croatia.
Hrvatski sažetak: Sposobnost p53 proteina da prepozna brojne unutarstanične i vanstanične stresove te nakon toga aktivira specifične biološke odgovora ključna je za sprječavanje nastanka zloćudnih tumora u sisavaca. Međutim, nepoznato je na koji su način različiti stresom-aktivirani signalni putevi integrirani na razini p53 proteina. Istraživanja grupe profesora Volarevića i drugih istraživača ukazale su na važnost specifičnih ribosomskih proteina u aktivaciji p53 proteina. Na temelju tih opažanja u ovom projektu postavljena je hipoteza da onkogeni stresovi aktiviraju tumor supresor p53 putem specifičnih ribosomskih proteina, čije mutacije mogu biti uzrok zloćudne preobrazbe stanice i otpornosti zloćudnih tumora u ljudi na terapiju. Projekt će se ostvariti u suradnji profesora Volarevića s Medicinskog fakulteta u Rijeci i profesora Dembića sa Sveučilišta u Oslu. Veliki potencijal ove suradnje proizlazi iz činjenica da obje istraživačke skupine imaju zajednički znanstveni interes, ali i komplementaran pristup predloženom istraživanju. Rezultati ovog projekta mogli bi potencijalno rezultirati unaprjeđenjem dijagnostike zloćudnih tumora, razvojem učinkovitijih protutumorskih lijekova i intelektualnim vlasništvom. Osim toga, projekt će unaprijediti znanstvene potencijale, kvalitetu istraživanja i obrazovanja u Hrvatskoj.
Amount requested from UKF: 1.191.842 HRK
Amount of matching funding: 238.368 HRK
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