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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