scholarly journals Thiol Redox Transitions in Cell Signaling: a Lesson from N-Acetylcysteine

2010 ◽  
Vol 10 ◽  
pp. 1192-1202 ◽  
Author(s):  
Tiziana Parasassi ◽  
Roberto Brunelli ◽  
Graziella Costa ◽  
Marco De Spirito ◽  
Ewa Krasnowska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Signaling ◽  
Global Gene Expression ◽  
Redox Status ◽  
Post Translational Modification ◽  
Redox Switch ◽  
Redox Transitions ◽  
Thiol Redox ◽  
Redox Switches ◽  
External Stimuli

The functional status of cells is under the control of external stimuli affecting the function of critical proteins and eventually gene expression. Signal sensing and transduction by messengers to specific effectors operate by post-translational modification of proteins, among which thiol redox switches play a fundamental role that is just beginning to be understood. The maintenance of the redox status is, indeed, crucial for cellular homeostasis and its dysregulation towards a more oxidized intracellular environment is associated with aberrant proliferation, ultimately related to diseases such as cancer, cardiovascular disease, and diabetes. Redox transitions occur in sensitive cysteine residues of regulatory proteins relevant to signaling, their evolution to metastable disulfides accounting for the functional redox switch. N-acetylcysteine (NAC) is a thiol-containing compound that is able to interfere with redox transitions of thiols and, thus, in principle, able to modulate redox signaling. We here review the redox chemistry of NAC, then screen possible mechanisms to explain the effects observed in NAC-treated normal and cancer cells; such effects involve a modification of global gene expression, thus of functions and morphology, with a leitmotif of a switch from proliferation to terminal differentiation. The regulation of thiol redox transitions in cell signaling is, therefore, proposed as a new tool, holding promise not only for a deeper explanation of mechanisms, but indeed for innovative pharmacological interventions.

scholarly journals KEAP1–NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity

2015 ◽  
Vol 469 (3) ◽  
pp. 347-355 ◽  
Author(s):  
Matthew Dodson ◽  
Matthew Redmann ◽  
Namakkal S. Rajasekaran ◽  
Victor Darley-Usmar ◽  
Jianhua Zhang
Keyword(s):  
Cell Signalling ◽  
Redox Status ◽  
Cellular Damage ◽  
Post Translational Modification ◽  
Redox Stress ◽  
Post Translational Modifications ◽  
Protein Thiols ◽  
Normal Metabolism ◽  
Thiol Redox ◽  
Cellular Pathogenesis

Maintaining cellular redox status to allow cell signalling to occur requires modulation of both the controlled production of oxidants and the thiol-reducing networks to allow specific regulatory post-translational modification of protein thiols. The oxidative stress hypothesis captured the concept that overproduction of oxidants can be proteotoxic, but failed to predict the recent finding that hyperactivation of the KEAP1–NRF2 system also leads to proteotoxicity. Furthermore, sustained activation of thiol redox networks by KEAP1–NRF2 induces a reductive stress, by decreasing the lifetime of necessary oxidative post-translational modifications required for normal metabolism or cell signalling. In this context, it is now becoming clear why antioxidants or hyperactivation of antioxidant pathways with electrophilic therapeutics can be deleterious. Furthermore, it suggests that the autophagy–lysosomal pathway is particularly important in protecting the cell against redox-stress-induced proteotoxicity, since it can degrade redox-damaged proteins without causing aberrant changes to the redox network needed for metabolism or signalling. In this context, it is important to understand: (i) how NRF2-mediated redox signalling, or (ii) the autophagy-mediated antioxidant/reductant pathways sense cellular damage in the context of cellular pathogenesis. Recent studies indicate that the modification of protein thiols plays an important role in the regulation of both the KEAP1–NRF2 and autophagy pathways. In the present review, we discuss evidence demonstrating that the KEAP1–NRF2 pathway and autophagy act in concert to combat the deleterious effects of proteotoxicity. These findings are discussed with a special emphasis on their impact on cardiovascular disease and neurodegeneration.

scholarly journals Extended Archaeal Histone-Based Chromatin Structure Regulates Global Gene Expression in Thermococcus kodakarensis

2021 ◽  
Vol 12 ◽  
Author(s):  
Travis J. Sanders ◽  
Fahad Ullah ◽  
Alexandra M. Gehring ◽  
Brett W. Burkhart ◽  
Robert L. Vickerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Regulation Of Gene Expression ◽  
Model Organism ◽  
Global Gene Expression ◽  
Single Amino Acid ◽  
Post Translational Modification ◽  
Histone Proteins ◽  
Thermococcus Kodakarensis ◽  
Archaeal Histone

Histone proteins compact and organize DNA resulting in a dynamic chromatin architecture impacting DNA accessibility and ultimately gene expression. Eukaryotic chromatin landscapes are structured through histone protein variants, epigenetic marks, the activities of chromatin-remodeling complexes, and post-translational modification of histone proteins. In most Archaea, histone-based chromatin structure is dominated by the helical polymerization of histone proteins wrapping DNA into a repetitive and closely gyred configuration. The formation of the archaeal-histone chromatin-superhelix is a regulatory force of adaptive gene expression and is likely critical for regulation of gene expression in all histone-encoding Archaea. Single amino acid substitutions in archaeal histones that block formation of tightly packed chromatin structures have profound effects on cellular fitness, but the underlying gene expression changes resultant from an altered chromatin landscape have not been resolved. Using the model organism Thermococcus kodakarensis, we genetically alter the chromatin landscape and quantify the resultant changes in gene expression, including unanticipated and significant impacts on provirus transcription. Global transcriptome changes resultant from varying chromatin landscapes reveal the regulatory importance of higher-order histone-based chromatin architectures in regulating archaeal gene expression.

Transcriptional profiling of iPSC-derived neurons with reciprocal monogenic CNV in 3p26.3 region

2020 ◽  
pp. 10-11
Author(s):  
М.Е. Лопаткина ◽  
В.С. Фишман ◽  
М.М. Гридина ◽  
Н.А. Скрябин ◽  
Т.В. Никитина ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
System Development ◽  
Transcriptional Profiling ◽  
Global Gene Expression ◽  
Nervous System Development ◽  
Number Variation ◽  
The Central Nervous System ◽  
Cntn6 Gene ◽  
Copy Number Changes

Проведен анализ генной экспрессии в нейронах, дифференцированных из индуцированных плюрипотентных стволовых клеток пациентов с идиопатическими интеллектуальными нарушениями и реципрокными хромосомными мутациями в регионе 3p26.3, затрагивающими единственный ген CNTN6. Для нейронов с различным типом хромосомных аберраций была показана глобальная дисрегуляция генной экспрессии. В нейронах с вариациями числа копий гена CNTN6 была снижена экспрессия генов, продукты которых вовлечены в процессы развития центральной нервной системы. The gene expression analysis of iPSC-derived neurons, obtained from patients with idiopathic intellectual disability and reciprocal microdeletion and microduplication in 3p26.3 region affecting the single CNTN6 gene was performed. The global gene expression dysregulation was demonstrated for cells with CNTN6 copy number variation. Gene expression in neurons with CNTN6 copy number changes was downregulated for genes, whose products are involved in the central nervous system development.

Sign in / Sign up

Export Citation Format

Share Document