NO and transcriptional regulation: from signaling to death.
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.
Zhou
Jie
J
Department of Cell Biology, Faculty of Biology, University of Kaiserslautern, Erwin-Schroedinger-Strasse, 67663 Kaiserslautern, Germany.
Brüne
Bernhard
B
D000818:Animals; D016923:Cell Death / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D026361:Reactive Nitrogen Species; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide