feedback loop
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IL-17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of linear ubiquitin chain assembly complex (LUBAC) as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- HEK293 buňky MeSH
- HeLa buňky MeSH
- kinasa I-kappa B genetika metabolismus MeSH
- lidé MeSH
- protein-serin-threoninkinasy genetika metabolismus MeSH
- receptory interleukinu-17 genetika metabolismus MeSH
- signální transdukce * MeSH
- zpětná vazba fyziologická * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In chordates, early separation of cell fate domains occurs prior to the final specification of ectoderm to neural and non-neural as well as mesoderm to dorsal and ventral during development. Maintaining such division with the establishment of an exact border between the domains is required for the formation of highly differentiated structures such as neural tube and notochord. We hypothesized that the key condition for efficient cell fate separation in a chordate embryo is the presence of a positive feedback loop for Bmp signaling within the gene regulatory network (GRN), underlying early axial patterning. Here, we therefore investigated the role of Bmp signaling in axial cell fate determination in amphioxus, the basal chordate possessing a centralized nervous system. Pharmacological inhibition of Bmp signaling induces dorsalization of amphioxus embryos and expansion of neural plate markers, which is consistent with an ancestral role of Bmp signaling in chordate axial patterning and neural plate formation. Furthermore, we provided evidence for the presence of the positive feedback loop within the Bmp signaling network of amphioxus. Using mRNA microinjections we found that, in contrast to vertebrate Vent genes, which promote the expression of Bmp4, amphioxus Vent1 is likely not responsible for activation of cephalochordate ortholog Bmp2/4. Cis-regulatory analysis of amphioxus Bmp2/4, Admp and Chordin promoters in medaka embryos revealed remarkable conservation of the gene regulatory information between vertebrates and basal chordates. Our data suggest that emergence of a positive feedback loop within the Bmp signaling network may represent a key molecular event in the evolutionary history of the chordate cell fate determination.
- MeSH
- crista neuralis cytologie metabolismus MeSH
- embryo nesavčí metabolismus MeSH
- kopinatci embryologie metabolismus MeSH
- kostní morfogenetické proteiny metabolismus MeSH
- messenger RNA metabolismus MeSH
- Oryzias embryologie metabolismus MeSH
- rozvržení tělního plánu MeSH
- signální transdukce * MeSH
- zpětná vazba fyziologická MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Developmental dysplasia and dislocation of the hip (DDH) is the most common type of lower limb deformity in pediatric orthopedics. The mechanism of the signaling pathway has been studied in depth. However, the role of epigenetic regulation, such as lncRNA, is still far from clear. In this study, we successfully established a rat model of DDH and demonstrated that H19 was down-regulated in the development of DDH. Further, we constructed H19 knockdown (KD) and overexpression chondrocytes. H19 KD suppressed the proliferation of normal chondrocytes, while overexpression of H19 promoted cell proliferation of DDH chondrocytes. Finally, we revealed that H19 bound to let-7 and inhibited its function, acting as a competing endogenous RNA. Down-regulation of H19 is closely associated with DDH progression and H19 is an important epigenetic factor that regulates the proliferation of chondrocytes. H19 may thus be a potential clinical marker for DDH diagnosis and treatment.
- MeSH
- chondrocyty fyziologie MeSH
- epigeneze genetická fyziologie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- mikro RNA genetika metabolismus MeSH
- novorozená zvířata MeSH
- potkani Wistar MeSH
- proliferace buněk fyziologie MeSH
- RNA dlouhá nekódující genetika metabolismus MeSH
- těhotenství MeSH
- vývojová kyčelní dysplazie genetika metabolismus MeSH
- zpětná vazba fyziologická fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- adenohypofýza fyziologie MeSH
- gonadotropiny MeSH
- hypofýza MeSH
- hypothalamus MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
Signal transduction in biological cells is effected by signaling pathways that typically include multiple feedback loops. Here we analyze information transfer through a prototypical signaling module with biochemical feedback. The module switches stochastically between an inactive and active state; the input to the module governs the activation rate while the output (i.e., the product concentration) perturbs the inactivation rate. Using a novel perturbative approach, we compute the rate with which information about the input is gained from observation of the output. We obtain an explicit analytical result valid to first order in feedback strength and to second order in the strength of input. The total information gained during an extended time interval is found to depend on the feedback strength only through the total number of activation/inactivation events.
- MeSH
- biologické modely * MeSH
- gating iontového kanálu fyziologie MeSH
- lidé MeSH
- počítačová simulace MeSH
- signální transdukce fyziologie MeSH
- ukládání a vyhledávání informací metody MeSH
- vápník metabolismus MeSH
- vápníkové kanály metabolismus MeSH
- zpětná vazba fyziologická fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: Ghrelin is predominantly produced by the stomach and the growth hormone (GH)-ghrelin feedback loop between the stomach and the pituitary gland has recently been suggested. The disruption of the gut-brain axis might be involved in bulimia nervosa (BN). METHODS: We investigated responses of plasma GH, ghrelin, and neuropeptide Y (NPY) concentrations to exercise or to exercise after the administration of the antilipolytic drug Acipimox (Aci) in seven BN patients and seven healthy women (C). Aci was administered 1h before exercise (45 min, 2 W/kg of lean body mass/LBM/). Ghrelin, GH, NPY, free fatty acids (FFA) and glycerol plasma levels were measured during the test using commercial kits. RESULTS: The exercise induced an increase in plasma GH, NPY and FFA in both groups and a decrease in plasma ghrelin levels only in BN patients. Exercise after Aci administration resulted in an increase in plasma GH, and a decrease in plasma ghrelin in both groups; NPY increased more in BN patients. Exercise-induced FFA increase was depressed after Aci. CONCLUSIONS: We conclude that the Aci-induced suppression in plasma ghrelin levels during exercise in both groups suggests a negative feedback of GH on ghrelin secretion. Observed changes in plasma FFA levels were not related to changes in GH and ghrelin levels.
- MeSH
- bulimia nervosa krev patofyziologie MeSH
- cvičení fyziologie MeSH
- dospělí MeSH
- experimenty na lidech MeSH
- ghrelin biosyntéza sekrece MeSH
- glycerol krev MeSH
- hypofýza účinky léků sekrece MeSH
- hypolipidemika aplikace a dávkování MeSH
- index tělesné hmotnosti MeSH
- kyseliny mastné neesterifikované krev MeSH
- lidé MeSH
- lidský růstový hormon biosyntéza sekrece MeSH
- neuropeptid Y krev MeSH
- pyraziny aplikace a dávkování MeSH
- studie případů a kontrol MeSH
- žaludek účinky léků metabolismus MeSH
- zpětná vazba fyziologická MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- 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
