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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
NO and transcriptional regulation: from signaling to death
1Department of Cell Biology, Faculty of Biology, University of Kaiserslautern, Erwin-Schroedinger-Strasse, 67663 Kaiserslautern, Germany.
Abstract:
It is nearly 20 years that nitric oxide (NO) entered the scene to become an integral component in understanding physiological and pathophysiological processes ranging from fine-tuned signaling to promoting cell demise. Among multiple activities attributed to NO we find regulation of gene expression. Although there is no evidence for direct NO-responsive DNA elements within promotor regions of eukaryotic genes numerous signaling pathways exist to understand NO-regulated gene expression. A characteristic feature of may transcription factors is their redox sensitivity as well as their low protein abundance in unstressed cells due to efficient 26S proteasomal degradation. Examples comprise the hypoxia inducible factor-1alpha (HIF-1alpha) and p53 (tumor suppressor p53). It became apparent that NO is able to mimic a hypoxic response by stabilizing HIF-1alpha and/or to affect viability decisions by accumulating p53. We will review recent molecular understanding how NO affects stability regulation of HIF-1alpha and p53, considering basic chemical reactions and cellular transducing pathways. Targeting HIF-1alpha and p53 by reactive nitrogen intermediates (RNI) may help to understand a sphere of NO-evoked transcriptional regulation ranging from cellular adaptation to death, i.e. apoptosis with important implications for medicine.
Insights
Nitric oxide (NO) regulates gene expression by stabilizing key proteins like hypoxia-inducible factor-1alpha (HIF-1alpha) and p53. This NO-mediated stabilization influences cellular adaptation and apoptosis, with significant medical implications.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Nitric oxide (NO) is a crucial signaling molecule involved in diverse physiological and pathophysiological processes.
- NO's role in regulating gene expression is complex, involving indirect signaling pathways rather than direct DNA interactions.
- Many transcription factors, such as HIF-1alpha and p53, are redox-sensitive and prone to degradation, influencing cellular responses.
Purpose of the Study:
- To review the molecular mechanisms by which nitric oxide affects the stability of HIF-1alpha and p53.
- To explore the implications of NO-mediated stabilization of these transcription factors in cellular adaptation and death pathways.
- To highlight the potential of targeting reactive nitrogen intermediates (RNI) for therapeutic interventions.
Main Methods:
- Review of existing literature on nitric oxide signaling pathways.
- Analysis of molecular mechanisms governing protein stability of transcription factors.
- Examination of cellular transducing pathways influenced by NO.
Main Results:
- Nitric oxide can stabilize hypoxia-inducible factor-1alpha (HIF-1alpha), mimicking hypoxic responses.
- NO influences the accumulation of p53 (tumor suppressor), affecting cell viability decisions.
- Reactive nitrogen intermediates (RNI) are key mediators of NO's effects on protein stability.
Conclusions:
- Nitric oxide plays a significant role in transcriptional regulation by modulating the stability of critical proteins like HIF-1alpha and p53.
- NO-induced stabilization of HIF-1alpha and p53 contributes to cellular adaptation and apoptosis.
- Understanding these NO-mediated pathways offers potential therapeutic targets for various medical conditions.
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