As species adapt to climatic changes, temperature-dependent functions of p53 in development, metabolism and cancer will adapt as well. Structural analyses of p53 epitopes interacting in response to environmental stressors, such as heat, may uncover physiologically relevant functions of p53 in cell regulation and genomic adaptations. Here we explore the multiple p53 elephant paradigm with an experimentally validated in silico model showing that under heat stress some p53 copies escape negative regulation by the MDM2 E3 ubiquitin ligase. Multiple p53 isoforms have evolved naturally in the elephant thus presenting a unique experimental system to study the scope of p53 functions and the contribution of environmental stressors to DNA damage. We assert that fundamental insights derived from studies of a historically heat-challenged mammal will provide important insights directly relevant to human biology in the light of climate change when 'heat' may introduce novel challenges to our bodies and health.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The p53 tumor suppressor is a transcription factor with roles in cell development, apoptosis, oncogenesis, aging, and homeostasis in response to stresses and infections. p53 is tightly regulated by the MDM2 E3 ubiquitin ligase. The p53-MDM2 pathway has coevolved, with MDM2 remaining largely conserved, whereas the TP53 gene morphed into various isoforms. Studies on prevertebrate ancestral homologs revealed the transition from an environmentally induced mechanism activating p53 to a tightly regulated system involving cell signaling. The evolution of this mechanism depends on structural changes in the interacting protein motifs. Elephants such as Loxodonta africana constitute ideal models to investigate this coevolution as they are large and long-living as well as having 20 copies of TP53 isoformic sequences expressing a variety of BOX-I MDM2-binding motifs. Collectively, these isoforms would enhance sensitivity to cellular stresses, such as DNA damage, presumably accounting for strong cancer defenses and other adaptations favoring healthy aging. Here we investigate the molecular evolution of the p53-MDM2 system by combining in silico modeling and in vitro assays to explore structural and functional aspects of p53 isoforms retaining the MDM2 interaction, whereas forming distinct pools of cell signaling. The methodology used demonstrates, for the first time that in silico docking simulations can be used to explore functional aspects of elephant p53 isoforms. Our observations elucidate structural and mechanistic aspects of p53 regulation, facilitate understanding of complex cell signaling, and suggest testable hypotheses of p53 evolution referencing Peto's Paradox.
- MeSH
- geny p53 MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- nádory * genetika MeSH
- protein - isoformy genetika metabolismus MeSH
- protoonkogenní proteiny c-mdm2 genetika metabolismus MeSH
- sloni * genetika metabolismus MeSH
- ubikvitinace MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tissue engineering benefits from novel materials with precisely tunable physical, chemical and mechanical properties over a broad range. Here we report a practical approach to prepare Bombyx mori silk fibroin hydrogels using the principle of non-solvent induced phase separation (NIPS). A combination of reconstituted silk fibroin (RSF) and methanol (non-solvent), with a final concentration of 2.5% w/v and 12.5% v/v respectively, maintained at 22 °C temperature turned into a hydrogel within 10 hours. Freeze-drying of this gel gave a foam with a porosity of 88%, a water uptake capacity of 89% and a swelling index of 8.6. The gelation kinetics and the loss tangent of the gels were investigated by rheometry. The changes in the morphology of the porous foams were visualized by SEM. The changes in RSF chemical composition and the relative fraction of its secondary structural elements were analyzed by ATR-FTIR along with Fourier self-deconvolution. And, the changes in the glass transition temperature, specific heat capacity and the relative fraction of crystallinity of RSF were determined by TM-DSC. Data suggested that RSF-water-methanol behaved as a polymer-solvent-non-solvent ternary phase system, wherein the demixing of the water-methanol phases altered the thermodynamic equilibrium of RSF-water phases and resulted in the desolvation and eventual separation of the RSF phase. Systematic analysis revealed that both gelation time and the properties of hydrogels and porous foams could be controlled by the ratios of RSF and non-solvent concentration as well as by the type of non-solvent and incubation temperature. Due to the unique properties we envisage that the herein prepared NIPS induced RSF hydrogels and porous foams can possibly be used for the encapsulation of cells and/or for the controlled release of both hydrophilic and hydrophobic drugs.
- MeSH
- biokompatibilní materiály chemie MeSH
- bourec chemie MeSH
- fibroiny chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- hydrogely chemie MeSH
- poréznost MeSH
- rozpouštědla chemie MeSH
- teplota MeSH
- tkáňové inženýrství MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
