ULOGA SUPRESORA TUMORA
 p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24

Jurada, Deana

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doctoral thesis

ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24

Rijeka: University of Rijeka, Faculty of Medicine, 2020. urn:nbn:hr:184:715800

Jurada, Deana

University of Rijeka
Faculty of Medicine
Department of Molecular Medicine and Biotechnology

Cite this document

APA 6th Edition

Jurada, D. (2020). ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24 (Doctoral thesis). Rijeka: University of Rijeka, Faculty of Medicine. Retrieved from https://urn.nsk.hr/urn:nbn:hr:184:715800

MLA 8th Edition

Jurada, Deana. "ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24." Doctoral thesis, University of Rijeka, Faculty of Medicine, 2020. https://urn.nsk.hr/urn:nbn:hr:184:715800

Chicago 17th Edition

Harvard

Jurada, D. (2020). 'ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24', Doctoral thesis, University of Rijeka, Faculty of Medicine, accessed 19 April 2024, https://urn.nsk.hr/urn:nbn:hr:184:715800

Vancouver

Jurada D. ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24 [Doctoral thesis]. Rijeka: University of Rijeka, Faculty of Medicine; 2020 [cited 2024 April 19] Available at: https://urn.nsk.hr/urn:nbn:hr:184:715800

IEEE

D. Jurada, "ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24", Doctoral thesis, University of Rijeka, Faculty of Medicine, Rijeka, 2020. Available at: https://urn.nsk.hr/urn:nbn:hr:184:715800

Cite this item: https://urn.nsk.hr/urn:nbn:hr:184:715800

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Metadata

Title	ULOGA SUPRESORA TUMORA p53 U REGULACIJI HOMEOSTAZE PROTEINA U STANICAMA HETEROZIGOTNIMA ZA GEN ZA RIBOSOMSKI PROTEIN L24
Title (english)	THE ROLE OF p53 TUMOR SUPPRESSOR IN PROTEIN HOMEOSTASIS REGULATION IN CELLS HETEROZYGOUS FOR RIBOSOMAL PROTEIN GENE L24
Author	Deana Jurada
Mentor	Siniša Volarević (mentor)
Committee member	Berislav Lisnić (predsjednik povjerenstva)
Committee member	Tihomir Balog (član povjerenstva)
Committee member	Ivana Mikolašević (član povjerenstva)
Committee member	Siniša Volarević (član povjerenstva)
Granter	University of Rijeka Faculty of Medicine (Department of Molecular Medicine and Biotechnology) Rijeka
Defense date and country	2020, Croatia
Scientific / art field, discipline and subdiscipline	BIOMEDICINE AND HEALTHCARE Basic Medical Sciences Human Genetics, Genomics and Proteomics
Universal decimal classification (UDC)	61 - Medical sciences 577 - Biochemistry. Molecular biology. Biophysics
Thesaurus (MESH - Medical Subject Headings)
Abstract	Cilj istraživanja: Heterozigotne mutacije RP u sisavaca uzrokuju razvojne anomalije i zloćudne tumore. Inaktivacija supresora tumora p53 u tim uvjetima sprječava nastanak razvojnih anomalija i potiče razvoj zloćudnih tumora. Međutim, molekularni mehanizmi putem kojih smanjeni izražaj RP uzrokuje promjene u stanicama i uloga p53 u tom kontekstu nepoznati su. Ključna pretpostavka ovog istraživanja je da heterozigotna inaktivacija RPL24 uzrokuje poremećaj homeostaze proteina te da p53 umanjuje negativne učinke tih promjena putem regulacije proteostatskih mehanizama. Ciljevi istraživanja su: 1. Izolirati fibroblaste iz wt, RPL24+/-, p53-/-, RPL24+/-:p53-/- embrija miševa (MEF, od engl. mouse embryonic fibroblasts); 2. Odrediti posljedice heterozigotnosti za RPL24 u MEF-ovima; 3. Odrediti ulogu p53 u RPL24+/- MEF-ovima. Materijal i metode: Istraživanja su provedena na MEF-ovima izoliranima iz wt, RPL24+/-, p53-/- i RPL24+/-:p53-/- embrija. Za određivanje posljedica heterozigotnosti za RPL24 u MEF-ovima i uloge p53 u tim procesima korištene su metode za analizu diobe stanica, sinteze proteina, signalnog puta mTORC1, proteasoma, autofagije, reaktivnih kisikovih radikala (ROS), agregata proteina te morfologije i funkcije mitohondrija. Rezultati: U RPL24+/- MEF-ovima smanjena je sinteza proteina ovisna o signalnom putu mTORC1, a povećana je aktivnost proteasoma i mTORC1-ovisne autofagije. Ti mehanizmi umanjuju proteotoksični stres u RPL24+/- MEF-ovima, ali nisu dostatni za njegovo potpuno sprječavanje, što se očituje nakupljanjem agregata proteina i ROS-a. Inaktivacija p53 u RPL24+/- MEF-ovima sprječava inhibiciju Sesn2/mTORC1-ovisne sinteze proteina i inhibira mTORC1-ovisnu autofagiju, što rezultira dodatnim nakupljanjem agregata proteina. Povećana sinteza proteina, smanjena količina ROS-a i p21 uslijed inaktivacije p53 u RPL24+/- MEF-ovima omogućuju njihovu ubrzanu diobu. Inaktivacija p53 u RPL24+/- MEF-ovima remeti normalnu morfologiju i smještaj mitohondrija i uzrokuje energetski stres. Zaključak: Razjašnjenje mehanizama putem kojih RPL24+/- uzrokuje promjene u MEF- ovima te uloge p53 u njihovoj regulaciji važne su za razumijevanje patogeneze bolesti karakteriziranih smanjenim izražajem RP poput anemije Diamond i Blackfan i zloćudnih tumora te mogu doprinijeti identifikaciji ciljeva za njihovo liječenje.
Abstract (english)	Aim of the study: Mutations of genes encoding RPs in mammals cause congenital malformations and malignant tumors. Inactivation of p53 tumor supressor under this conditions prevents congenital malformations and facilitates the development of malignant tumors. However, molecular mechanisms underlying these processes are unknown. I hypothesized that heterozygous inactivation of RPL24 leads to perturbation of cellular proteostasis and that p53 modulates the pathological phenotype by regulating proteostatic mechanisms. Specific aims of this research are: 1.To isolate fibroblasts from wt, RPL24+/- , p53-/-, RPL24+/-:p53-/- mouse embryos (MEFs), 2. To identify the consequences of RPL24 heterozygosity in MEFs, 3. To determine the role of p53 in RPL24+/- MEFs. Materials and methods: wt, RPL24+/-, p53-/-, RPL24+/-:p53-/- MEFs are used in this study. To determine the consequences of RPL24 heterozygosity on protein homeostatsis and the role of p53 in that processes, I used a number of methods to assess cell division, protein synthesis, reactive oxygen species (ROS), protein aggregates and mitochondria morfology and function as well as activity of mTORC1 signaling pathway, proteasomes and autophagy. Results: In RPL24+/- MEFs mTORC1-dependant protein synthesis is downregulated, whereas proteasomal and autophagosomal degradation are upregulated. However, activation of these proteostatic mechanisms are not sufficient to fully prevent formation of protein aggregates and ROS in these MEFs. Inactivation of p53 in RPL24+/- MEFs prevents Sesn2/mTORC1-dependant inhibition of protein synthesis and inhibits autophagy, which enhances the accumulation of protein aggregates. Despite the presence of protein aggregates, increased protein synthesis, reduced amount of ROS and p21 upon p53 inactivation in RPL24+/- MEFs enable accelaration of their proliferation. Finally, inactivation of p53 in RPL24+/- MEFs disrupts normal mitochondria morphology and cellular localization leading to the energetic stress. Conclusion: These results will enable better understanding of the molecular mechanisms by which perturbations in ribosome biogenesis lead to Diamond and Blackfan anemia and malignant tumors and they may reveal therapeutic liabilities in these diseases.
Keywords
Keywords (english)
Language	croatian
URN:NBN	urn:nbn:hr:184:715800
Promotion	2021
Study programme	Title: Biomedicine Postgraduate (doctoral) study programme Study programme type: university Study level: postgraduate Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
Type of resource	Text
File origin	Born digital
Access conditions	Access restricted to students and staff of home institution
Terms of use
Repository	Repository of the University of Rijeka, Faculty of Medicine
Created on	2021-03-03 00:07:28

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