ABSTRACT
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It is widely accepted that nitric oxide (NO) is an important signaling molecule that shapes several physiological and patho-physiological processes. Among multiple activities attributed to NO, we find regulation of gene expression. Although no evidence exists regarding whether direct NO-responsive DNA elements within promotor regions of eukaryotic genes, numerous transcription factors are affected either resulting in increased or decreased expression of target genes. In part, this is compatible with the interference of NO with signaling circuits upstream of transcription factors that, in turn, will modulate their activity. A characteristic feature of several transcription factors is their redox sensitivity as well as their
low protein abundance in unstressed cells due to efficient 26S proteasomal degradation. One example is the hypoxia inducible factor-1α (HIF-1α) known as the master regulator allowing adaptation toward decreased oxygen availability. We now appreciate that NO under normoxic conditions mimics a hypoxic response by stabilizing HIF-1α. Under hypoxic conditions, however, NO destabilizes HIF-1α and thus reverses hypoxic adaptation. This chapter summarizes recent molecular understanding of how NO affects stability regulation of HIF1α under normoxia vs. hypoxia and discusses patho-physiological consequences. Targeting HIF-1α by NO expands the sphere of NO actions with medical-related consequences for conditions such as ischemia/reperfusion, angiogenesis, or tumor biology.
