Regulace exprese proteinu p53 je kritická pro kontrolu jeho aktivity v normálních i poškozených buňkách. Velmi dobře je popsána úloha E3 ubikvitin ligázy MDM2, která je za normálních podmínek zodpovědná za degradaci p53 v proteazomu a je esenciální při kontrole aktivity p53 během vývoje organizmu. Nadměrná exprese MDM2 spolu s některými dalšími E3 ligázami podílejícími se rovněž na regulaci stability p53 byla prokázána u řady lidských nádorů, což jen podtrhuje význam posttranslační regulace hladiny proteinu p53. Za stresových podmínek se hladina TP53 na úrovni mRNA zásadně nemění, naopak vše nasvědčuje tomu, že syntéza proteinu p53 je řízena především na úrovni iniciace translace, což představuje významný mechanizmus zodpovědný za kontrolu exprese p53. Na druhou stranu současné práce ukazují, že i TP53 mRNA hraje důležitou roli při regulaci aktivity proteinu p53 v buňce. Proto jsme se v této práci zaměřili a diskutujeme mechanizmy zodpovědné za kontrolu syntézy proteinu p53 a jejich úlohu při regulaci p53 aktivity za normálních podmínek a při různých typech stresu.
The regulation of p53 expression levels is critical in controlling p53 activity in normal and damaged cells. This is well illustrated by the E3 ubiquitin ligase MDM2 that targets p53 for proteasomal degradation under normal conditions and is essential for controlling p53 activity during development. MDM2 is over-expressed in human cancers and together with some other E3 ligases that have also been implicated in controlling p53 stability, which emphasises the importance of post-translational regulation of p53 expression. At the level of synthesis, TP53 mRNA levels do not change in response to stresses and it is instead its rate of translation initiation that provides the mechanism of choice for expression control. More recent work has shown that TP53 mRNA plays an important role in mediating the cellular regulation of p53 activity. We will discuss the regulation of p53 synthesis and its implications for controlling p53 activity under normal conditions and during different types of stress response.
- Klíčová slova
- syntéza p53, RNA-vazebné proteiny, odpověď na stres,
- MeSH
- fyziologický stres MeSH
- IRES MeSH
- lidé MeSH
- messenger RNA MeSH
- nádorový supresorový protein p53 * fyziologie MeSH
- nádory genetika patofyziologie MeSH
- oxidační stres MeSH
- poškození DNA MeSH
- protein - isoformy MeSH
- proteosyntéza * MeSH
- protoonkogenní proteiny c-mdm2 MeSH
- protoonkogenní proteiny * genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The function and regulation of MDM2 as a component of a p53-dependent negative feedback loop has formed a core paradigm in the p53 field. This concept, now 20 years old, has been solidified by fields of protein science, transgenic technology, and drug discovery in human cancer. However, it has been noted that a simple negative feedback loop between p53 and MDM2 lacks an intrinsic "activating" step that counteracts this inhibition and permits oscillation of the feedback to occur as p53 is switched on and off. More recent work has identified a solution to the missing piece of the picture that counters the negative feedback loop, which is MDM2 itself. Under conditions of genotoxic stress, MDM2 helps to activate p53 by increasing its rate of protein synthesis. This simple observation makes certain aspects of the p53 response more comprehensible such as why MDM2 is upregulated by p53 early on following DNA damage and how phosphorylation of MDM2 at the C-terminal Ser395 by ATM translates into p53 activation. The latter acts by inducing allosteric changes in the RING domain of MDM2 that expose its RNA binding pocket, support p53 synthesis, and suppress its degradation. This allosteric nature of MDM2 in the C-terminus mirrors the allosteric effects of the binding of small molecules to the p53 interacting pocket at the N-terminus of MDM2, which opens the core domain of MDM2 to central domains of p53, which controls p53 ubiquitination. Thus, the highly allosteric nature of MDM2 provides the basis for dynamic protein-protein interactions and protein-RNA interactions through which MDM2's activity is regulated in p53 protein destruction or in p53 protein synthesis. We discuss these mechanisms and how this information can be exploited for drug development programs aimed at activating p53 via targeting MDM2.
- Publikační typ
- časopisecké články MeSH
