The transcription factor NF-κB (nuclear factor κB) serves to up-regulate gene expression in response to precarious signals such as the pro-inflammatory cytokines TNF (tumour necrosis factor) and IL-1 ...(interleukin 1). In the present study we show that stimulation of cells with TNF or IL-1 results in a profound conformational switch of the NF-κB subunit p65, as revealed by limited proteolysis assays. We also describe the identification of a conformation-specific monoclonal antibody that preferentially immunoprecipitates the inducibly refolded p65 protein. The cytokine-triggered reconfiguration of p65 mainly occurs for p65 contained in the nuclear fraction. Phosphorylations serve as the central driving force for the inducible reconfiguration of p65. Accordingly, mutation of single phosphorylation sites in the C-terminal transactivation domain led to large conformational changes which result in strongly decreased ubiquitination and also in differential protein-protein interactions. Induced conformational changes of p65 thus increase the intramolecular flexibility and therefore expand and specify the repertoire of possible protein-protein interactions. Constitutively bound chaperones of the Hsp (heat-shock protein)/Hsc70 (heat-shock cognate protein, 73 kDa) family are not important for the cytokine-induced conformational switch, but rather control the fidelity of protein rearrangement. Accordingly, pharmacological inhibition of Hsp/Hsc70 interferes with p65-triggered gene expression.
Confocal Raman spectroscopy has emerged as a major, versatile workhorse for the non-invasive characterization of graphene. Although it is successfully used to determine the number of layers, the ...quality of edges, and the effects of strain, doping and disorder, the nature of the experimentally observed broadening of the most prominent Raman 2D line has remained unclear. Here we show that the observed 2D line width contains valuable information on strain variations in graphene on length scales far below the laser spot size, that is, on the nanometre-scale. This finding is highly relevant as it has been shown recently that such nanometre-scaled strain variations limit the carrier mobility in high-quality graphene devices. Consequently, the 2D line width is a good and easily accessible quantity for classifying the crystalline quality, nanometre-scale flatness as well as local electronic properties of graphene, all important for future scientific and industrial applications.
The nuclear factor kappa B (NF-κB) signaling system, a key regulator of immunologic processes, also affects a plethora of metabolic changes associated with inflammation and the immune response. ...NF-κB–regulating signaling cascades, in concert with NF-κB–mediated transcriptional events, control the metabolism at several levels. NF-κB modulates apical components of metabolic processes including metabolic hormones such as insulin and glucagon, the cellular master switches 5' AMP-activated protein kinase and mTOR, and also numerous metabolic enzymes and their respective regulators. Vice versa, metabolic enzymes and their products also exert multilevel control of NF-κB activity, thereby creating a highly connected regulatory network. These insights have resulted in the identification of the noncanonical IκB kinase kinases IκB kinase ɛ and TBK1, which are upregulated by overnutrition, and may therefore be suitable potential therapeutic targets for metabolic syndromes. An inhibitor interfering with the activity of both kinases reduces obesity-related metabolic dysfunctions in mouse models and the encouraging results from a recent clinical trial indicate that targeting these NF-κB pathway components improves glucose homeostasis in a subset of patients with type 2 diabetes.
Cyclin-dependent kinases (CDKs) exert a variety of functions through regulation of the cell cycle and gene expression, thus implicating them in diverse biological processes. Recent studies have ...deciphered the molecular mechanisms employed by nuclear CDKs to support the expression of inflammatory mediators. Induced transcription of many proinflammatory genes is increased during the G1 phase of the cell cycle in a CDK-dependent manner. This process involves the cytokine-induced recruitment of CDK6 to the nuclear chromatin fraction where it associates with transcription factors of the NF-κB, STAT, and AP-1 families. The ability of CDK6 to trigger the expression of VEGF-A and p16INK4A and to recruit the NF-κB subunit p65 to its target sites is largely independent of its kinase function. The involvement of CDKs in proinflammatory gene expression also allows therapeutic targeting of their functions to interfere with tumor-promoting inflammation or chronic inflammatory diseases.
The role of hypoxia-inducible factor (HIF)-1α in the control of proliferation under non-hypoxic conditions has been investigated in numerous studies, but does not yield a coherent picture. Therefore, ...we conducted this meta-analysis of existing literature to systematically evaluate the role of HIF-1α, based on a number of inclusion and exclusion criteria. Studies analyzing non-transformed, primary cells showed a largely heterogeneous distribution of pro-proliferative, anti-proliferative or absent functions for HIF-1α, which are co-determined by several parameters, including the type and age of the cell and its localization in tissues and organs. In contrast, the analyses of tumor cells showed a predominantly pro-proliferative role of HIF-1α by cell-intrinsic and cell-extrinsic molecular mechanism not yet understood.
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Open questions in the NF-κB field Bacher, Susanne; Schmitz, M Lienhard
Biochimica et biophysica acta. Molecular cell research,
02/2024, Letnik:
1871, Številka:
2
Journal Article
Recenzirano
A variety of stress signals leads to activation of the inducible transcription factor NF-κB, one of the master regulators of the innate immune response. Despite a wealth of information available on ...the NF-κB core components and its control by different activation pathways and negative feedback loops, several levels of complexity hamper our understanding of the system. This has also contributed to the limited success of NF-κB inhibitors in the clinic and explains some of their unexpected effects. Here we consider the molecular and cellular events generating this complexity at all levels and point to a number of unresolved questions in the field. We also discuss potential future experimental and computational strategies to provide a deeper understanding of NF-κB and its coregulatory signaling networks.
Context
Multifunctional rural landscapes are social-ecological systems that represent a link between nature and culture. They are characterized by the conservation and protection of ecological ...processes, natural resources and biocultural diversity. The conservation of these landscapes is mainly based on the establishment of Protected Natural Areas (PAs) whose regulatory schemes have often promoted their degradation.
Objectives
We evaluate the effectiveness of the conservation strategies of the Natural Park category in the protection and maintenance of rural cultural landscapes. We analyse at a regional and local scale both the dynamics of land-uses and the socioeconomic structure of the local populations involved, identifying the main social-ecological indicators of change in the protected landscape.
Methods
We apply a methodological approach, based on geoprocessing tools and multivariate analysis, to examine social-ecological changes in rural cultural landscapes after the establishment of a network of PAs. The designed method allows us to infer the ecological and socioeconomic resilience of protected landscapes.
Results
Conservation efforts have tended to underestimate rural landscapes in favour of natural ones, mainly forest systems, and have not been able to prevent the processes of abandonment and degradation of protected landscapes. A simplification of the land-use systems dependent on traditional farming practices is observed. This implies the loss of both the multifunctionality of rural landscapes and their resilience to environmental changes. The key socioeconomic indicators identified highlight the deterioration of the rurality of protected landscapes.
Conclusions
Our social-ecological approach is a useful tool to evaluate the effectiveness of PAs. Protection of landscape is related to the decline of traditional agricultural systems and rewilding through land abandonment. Culturalness is necessary to promote the management and conservation of rural landscapes from a holistic perspective.
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