HIF-1alpha and p53 as targets of NO in affecting cell proliferation, death and adaptation.

During the past years nitric oxide (NO) signaling became an integral component in understanding physiological and pathophysiological processes of cell proliferation, death or cellular adaptation. Among other activities NO affects multiple targets that allow regulation of gene expression. Although there is no evidence for direct NO-responsive DNA elements within promotor regions of eukaryotic genes numerous indirect signaling pathways exist to explain NO-regulated gene expression. A characteristic feature of some transcription factors such as hypoxia inducible factor-1alpha (HIF-1alpha) or p53 (tumor suppressor p53) is their low protein abundance in unstressed cells due to efficient 26S proteasomal degradation of the protein. Characteristically, the protein amount of HIF-1alpha or p53 is increased steeply upon hypoxic stress or mechanisms that require activation of "guardian of the genome", i.e. p53. Current available data illustrate that NO is endowed with the ability to mimic a hypoxic response by stabilizing HIF-1alpha and/or to accumulate p53 and thus to affect viability decisions. Here we review recent advances in understanding molecular mechanisms how NO affects stability regulation of HIF-1alpha and p53. Moreover, we summarize existing concepts how HIF-1alpha and p53 interact to direct proliferation, death or adaptation. Considering HIF-1alpha and p53 as targets of reactive nitrogen intermediates (RNI) may provide insights into basic chemical reactions, biochemical signal transduction pathways with broad implications for medicine.