Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.
- MeSH
- bakteriální léková rezistence účinky léků fyziologie MeSH
- cílená molekulární terapie metody MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- nádorový supresorový protein p53 antagonisté a inhibitory genetika metabolismus MeSH
- nádory farmakoterapie MeSH
- protinádorové látky farmakologie MeSH
- protoonkogenní proteiny c-mdm2 antagonisté a inhibitory genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.
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- 3' nepřekládaná oblast genetika MeSH
- 5' nepřekládaná oblast genetika MeSH
- fyziologický stres genetika MeSH
- lidé MeSH
- ligandy MeSH
- messenger RNA genetika MeSH
- nádorový supresorový protein p53 genetika MeSH
- protoonkogenní proteiny c-mdm2 metabolismus MeSH
- riboswitch genetika MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Východiská: Proteíny HDM2 a HDMX sú hlavné negatívne regulátory tumorového supresoru p53. Ich úlohou je udržiavať nízku hladinu proteínu p53 za normálnych podmienok. V stresových podmienkach je však táto negatívna regulácia prerušená, čo umožní aktiváciu p53 dráhy. V mnohých ľudských nádoroch, ktoré si zachovávajú wild type p53, bola nájdená nadmerná expresia proteínov HDM2 a HDMX, ako napr. v sarkóme. A tak okrem inaktivujúcej mutácie v géne pre proteín p53, modulácia expresie proteínov HDM2 a HDMX predstavuje alternatívny mechanizmus inaktivácie signálnej dráhy p53. Cieľ: V tomto zhrnutí stručne predstavíme funkciu proteínov HDM2 a HDMX, zhrnieme informácie o zvýšenom výskyte proteínov HDM2 a HDMX v ľudských nádoroch, jeho možné príčiny a predstavíme rôzne prístupy k potenciálnej liečbe nádorov založenej na cielení na proteíny HDM2 a HDMX. Záver: HDM2 a HDMX sa stali zaujímavými cieľmi protinádorovej terapie, kedy prerušenie negatívnej regulácie p53 pomocou látok, ako napr. nutlinov, môže viesť k reaktivácii p53 odpovede a k potlačeniu rakovinového bujenia. Nové poznatky o funkcii a štruktúre proteínov HDM2, HDMX a p53 umožňujú návrh nových druhov terapeutík, čo môže prispieť k špecifickej liečbe a efektívnejšej odpovedi pacientov. Mnohé z látok sú už testované v rámci klinických štúdií fáze I, II a III.
Background: HDM2 and HDMX proteins are key negative regulators of the tumor suppressor p53. Under normal conditions, p53 protein expression is maintained at a low level, whereas under stress conditions, this negative regulation is alleviated to increase the p53 level. HDM2 and HDMX are overexpressed in many cancer types, mainly in tumors with wild type p53, such as sarcomas. In addition to an inactivating mutation in the TP53 gene, HDM2 and HDMX overexpression represents another kind of p53 inactivation pathway. Aim: In this review, we first briefly describe the roles of HDM2 and HDMX proteins and then the increased occurrence of their overexpression and the possible causes of this overexpression in different human cancer types as well as therapeutic approaches targeting HDM2 and HDMX for the treatment of human cancer. Conclusion: HDM2 and HDMX are important therapeutic targets. The interruption of their negative effect on p53 pathway by compounds such as nutlins, leads to the reactivation of the p53 pathway. However, a deeper understanding of HDM2-HDMX-p53 structure and function will enable the identification of new therapeutic strategies that could help to provide more specific and more efficient therapies for cancer patients. Several small molecules and peptides are the subject of clinical testing in phase I, II and even III trials.
- MeSH
- lidé MeSH
- nádorový supresorový protein p53 * metabolismus MeSH
- nádory * patofyziologie terapie MeSH
- onkogenní proteiny metabolismus MeSH
- protoonkogenní proteiny c-mdm2 * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Interferon-inducible protein 16 (IFI16) is a member of the HIN-200 protein family, containing two HIN domains and one PYRIN domain. IFI16 acts as a sensor of viral and bacterial DNA and is important for innate immune responses. IFI16 binds DNA and binding has been described to be DNA length-dependent, but a preference for supercoiled DNA has also been demonstrated. Here we report a specific preference of IFI16 for binding to quadruplex DNA compared to other DNA structures. IFI16 binds to quadruplex DNA with significantly higher affinity than to the same sequence in double stranded DNA. By circular dichroism (CD) spectroscopy we also demonstrated the ability of IFI16 to stabilize quadruplex structures with quadruplex-forming oligonucleotides derived from human telomere (HTEL) sequences and the MYC promotor. A novel H/D exchange mass spectrometry approach was developed to assess protein interactions with quadruplex DNA. Quadruplex DNA changed the IFI16 deuteration profile in parts of the PYRIN domain (aa 0-80) and in structurally identical parts of both HIN domains (aa 271-302 and aa 586-617) compared to single stranded or double stranded DNAs, supporting the preferential affinity of IFI16 for structured DNA. Our results reveal the importance of quadruplex DNA structure in IFI16 binding and improve our understanding of how IFI16 senses DNA. IFI16 selectivity for quadruplex structure provides a mechanistic framework for IFI16 in immunity and cellular processes including DNA damage responses and cell proliferation.
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- DNA chemie genetika metabolismus MeSH
- fosfoproteiny chemie genetika metabolismus MeSH
- G-kvadruplexy * MeSH
- jaderné proteiny chemie genetika metabolismus MeSH
- konformace nukleové kyseliny MeSH
- konformace proteinů MeSH
- lidé MeSH
- responzivní elementy genetika MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
