Development of yeast-based assays to study p53 family proteins: Identification of new small molecule modulators
Başlık:
Development of yeast-based assays to study p53 family proteins: Identification of new small molecule modulators
Yazar:
Leão, Mariana Valencia Castanheira Ferreira, author.
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (165 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-07C.
Özet:
The p53 family consists of three members, p53, p63 and p73 with a central role in the control of cell differentiation, proliferation and death, among others. This family of proteins is therefore considered a key therapeutic target in cancer. Although the intense research around these proteins, the biological and pharmacological profile of several p53 family members remains far from being completely understood, particularly due to the high complexity of the p53 pathway in mammalian cells. The function of these proteins is negatively regulated by interactors, such as murine double minute (MDM)2 and MDMX. However, contrary to p53 and p73, the regulation of p63 by MDM2/MDMX is still controversial. In spite of this, the inhibition of these interactions with MDM2/MDMX represents a promising therapeutic strategy to reactivate p53 family proteins in tumours. Despite the huge number of inhibitors of the p53-MDM2 interaction discovered in the last few years, only few inhibitors of the p53-MDMX interaction and dual inhibitors of the p53- MDM2/MDMX interaction have been reported. Similarly, inhibitors of the p63 and 73 interaction with MDM2/MDMX remain mostly unknown.
In the present thesis, the yeast Saccharomyces cerevisiae was used as a cell model for an independent analysis of human p53, p63 (full length and truncated forms) and p73 (full length) in a simplified eukaryotic cell system. Using this approach, several aspects of the biology of p53 family proteins were studied, particularly their regulation by MDM2/MDMX. Several similarities among the activities of the different p53 family proteins expressed in yeast were observed. In fact, all of them induced growth inhibition associated with S-phase cell cycle arrest and an autophagic cell death, reactive oxygen species generation, increase of actin depolarization and protein expression levels. Despite this, different sensitivities to the autophagosome pathway, to the inhibitory effect of MDM2 and MDMX, and to small molecule modulators of their interactions with MDM2/MDMX clearly emerged.
Notlar:
School code: 5896
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678864.1) | 678864-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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