Interakcije proteina p53 te karakterizacija stanica otpornih na ciljanu terapiju vemurafenibom u melanomu čovjeka

doctoral thesis

• Title (english): Protein interactions of p53 and characterization of cells resistant to targeted therapy by vemurafenib in human melanoma
• Author: Martina Radić
• Mentor: Maja Herak-Bosnar (mentor)
• Committee member: Neda Slade (predsjednik povjerenstva)
• Committee member: Igor Weber (član povjerenstva)
• Committee member: Maja Matulić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2021-03-29, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 577 - Biochemistry. Molecular biology. Biophysics

Abstract

Melanom je jedan od najagresivnijih tumora čovjeka te je vodeći uzrok smrti oboljelih od tumora kože. Iako su saznanja o molekularnoj pozadini bolesti dovela su do otkrića novih terapija, dugotrajno liječenje onemogućeno je pojavom otpornosti. Iznenađujuće, iako je u melanomu tumorski supresor p53 rijetko mutiran, ne obavlja svoju funkciju u suzbijanju tumora.
Glavni fokus našeg rada otkrivanje je mehanizama otpornosti na ciljanu terapiju vemurafenibom te istraživanje proteinskih interakcija proteina p53 koje bi mogle biti jedan od razloga njegove inaktivacije. Razvili smo i okarakterizirali stanice melanoma otporne na vemurafenib te proučili interakcije proteina p53 s članovima proteinskih porodica p53, NME i GLI. Naši rezultati pokazuju aktivaciju signalnog puta MAPK i PI3K/AKT pojavom otpornosti na terapiju. Također, pokazali smo da protein p53 ostvaruje interakcije s pojedinim izoformama proteina p53 i p73, ali ne i s članovima porodice NME i GLI. Ovim radom smo ukazali na moguću važnost interakcija unutar porodice p53.

Abstract (english)

Melanoma is one of the most aggressive human tumors and the leading cause of death of skin cancer patients. Even though the molecular understanding of underlying mechanisms driving melanoma has led to the discovery of new therapies, long-term success has been hampered by the development of drug resistance. Surprisingly, although the tumor suppressor p53 is rarely mutated in melanoma, its tumor-suppressive function seems to be impaired.
The main focus of this work is the discovery of mechanisms of resistance to targeted therapy by vemurafenib together with the study of protein interactions of p53 that could be one of the causes of its inactivation. We developed and characterized vemurafenib-resistant melanoma cells and studied the interactions of p53 with members of the p53, NME, and GLI protein families. Our results show activation of the MAPK and PI3K/AKT signaling pathways after the development of resistance. We further show that the p53 protein interacts with individual isoforms of the p53 and p73 proteins, but not with members of the NME and GLI families. In this work, we pointed out the possible importance of interactions within the p53 family.

• Keywords: melanom; p53; NME; GLI; ciljana terapija; vemurafenib
• Keywords (english): melanoma; p53; NME; GLI; targeted therapy; vemurafenib
• Language: croatian
• URN:NBN: urn:nbn:hr:217:320600
• Promotion: 2021
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-03-29
• Created on: 2021-09-21 10:43:07