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Identifier 000441096
Title Historical retrospective analysis of the p53 gene and new perspectives
Alternative Title Ιστορική αναδρομή του γονιδίου P53 και νέες προοπτικές
Author Ιορδανίδου, Καλλιόπη
Thesis advisor Ζουμπουρλής, Βασίλειος
Reviewer Αγγελάκη, Σοφία
Σουρβίνος, Γεώργιος
Abstract The tumor suppressor gene, TP53, is the most frequently mutated gene in human cancers. Although this gene was firstly identified in simian virus 40- transformed mouse cells in 1979, it took several years to be established as a tumor suppressor. Finally, p53 protein was proved to play a crucial role in many cellular processes and induce apoptosis whenever is necessary, deservedly dubbed as the ‘guardian of genome’. Research revealed that p53 protein comprises of three main domains: N-terminal domain (NTD), DNA-binding domain (DBD) and C-terminal (CTD) which are responsible for its function as a transcription factor. p53 has both transcription-dependent and -independent functions. It is involved in a wide range of cellular processes such as cell cycle arrest, apoptosis, DNA damage repair, cellular senescence, angiogenesis, metabolism, ROS regulation, differentiation and development. TP53 is mutated in approximately 50-60% of human cancer cases and most of these mutations are missense mutations localized in 6 specific sites of DNA-binding domain. This results in loss-of-function (LOH) because mutated p53 has no longer the ability to bind DNA and act as a transcription factor. In some cases, besides LOH, mutated p53 protein acquires new properties, known as Gain-of-function (GOF), which include protein-protein interactions as it is unable to bind DNA. Significant role in p53 research had the discovery of MDM2/MDM4 proteins which block the activity of p53, by binding on the p53’s transactivation domain (N’ terminal) under normal conditions and lead to proteasome-mediated degradation of p53. This procedure was found to be disrupted in many cancers leading to continuous p53 inhibition which is destructive for the cells. The above knowledge on p53 functions and mutants led to the discovery of p53-targeted anti-cancer therapies such as gene therapies, therapies of p53 restoration, use of MDM2/MDM4 inhibitors, GOF targeting, immunotherapy, etc. Many of these treatments are currently tested in clinical trials, with few compounds having reached phase III (e.g. ARP-246, a p53 reactivator).
Language English
Subject MDM2-P53 interaction
Mutant P53 proteins
P53 functions
P53 protein
P53 structure
P53-related anti-cancer treatments
Tumor suppressor
Αντικαρκινικές p53-θεραπείες
Λειτουργίες της P53 πρωτεϊνης
Μεταλλαγμένες P 53 πρωτεϊνες
Ογκοκατασταλτικό γονίδιο
Πρωτεϊνη P53
Issue date 2021-07-30
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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