Transcription factors p53 and HIF-1alpha as targets of nitric oxide.
It is widely recognized that the production of nitric oxide (NO) from L-arginine metabolism is an essential determinate of diverse signalling cascades throughout the body, with a major impact during nonspecific host defence. Biological actions of NO and derived species comprise physiological as well as pathological entities, with an impressive and steadily growing number of signalling pathways and/or protein targets being involved. It is now appreciated that NO not only acts as an effector molecule but also as an autocrine as well as paracrine modulator of rapid and delayed cellular responses. Among multiple targets the tumour suppressor p53 and the hypoxia inducible factor-1alpha (HIF-1alpha) emerged. Accumulation of p53 in response to NO delivery may account for an interference in cell cycle progression and/or initiation of apoptosis that is found in close correlation with inducible NO synthase (NOS) expression. Quite similarly, accumulation of HIF-1alpha not only occurs during hypoxia, but also under conditions of NO delivery, thus mimicking a situation of reduced oxygen availability. Interestingly, p53 and HIF-1alpha share regulatory elements that cause protein stabilization in part as a result of impaired ubiquitin-evoked protein degradation. Here, we summarize current knowledge on the impact of NO on p53- and HIF-1alpha-stabilization and we will discuss pathophysiological consequences. These examples may help to shape and refine current concepts of NO action with an emphasis on transcription factor regulation.
Brüne
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B
Department of Medicine IV-Experimental Division, Faculty of Medicine, University of Erlangen-Nürnberg, Loschgestrasse 8, 91054, Erlangen, Germany. bernhard.bruene@rzmail.uni-erlangen.de
von Knethen
A
A
Sandau
K B
KB
D000818:Animals; D017209:Apoptosis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008954:Models, Biological; D009569:Nitric Oxide / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide