The emergence of complex multicellular organisms during evolution required systems for ensuring adequate cellular oxygenation. Any reader doubting the veracity of this statement is invited to hold his or her breath while reading the remainder of this article. For this reason, considerable effort has been devoted to understanding how cells in higher eukaryotes sense and respond to changes in oxygen availability. Over the years a number of models were put forth to explain how cells sense oxygen. Unfortunately, these models were complex and, at times, contradictory. For example, some models suggested that a decrease in intracellular reactive oxygen species (ROS) gave rise to a low oxygen (hypoxia) signal whereas other models suggested the opposite (Semenza 1999). Likewise, some models suggested that mitochondria were categorically required for delivery of a hypoxic signal whereas others did not (Chandel et al. 1998; Srinivas et al. 2001; Vaux et al. 2001). Approximately one year ago, however, a surprisingly simple and conceptually attractive picture of oxygen sensing began to emerge. At the heart of this model is a posttranslational modification, hydroxylation, that is inherently oxygen-dependent, and a transcription factor called HIF (hypoxia-inducible factor).

It has been known for some time that HIF is a master regulator of genes that are activated by low oxygen levels (Semenza 2001). These genes encode proteins that play roles in the acute and chronic adaptation to oxygen deficiency. The former include proteins involved in regulating glucose uptake, glucose metabolism, and extracellular pH, which allow for continued energy generation in a hypoxic environment. The latter include proteins involved in angiogenesis and erythropoiesis, which increase blood vessel density and blood oxygen-carrying capacity, respectively. HIF is a heterodimer consisting of one of three alpha subunits (HIF-1α, HIF-2α, or HIF-3α) and a beta subunit (HIF-1ß, also called Aryl Hydrocarbon Nuclear Translocator, or ARNT). As its name suggests, HIF is only active under hypoxic conditions. This is because the alpha subunits are rapidly degraded in the presence of oxygen due to polyubiquitination by an E3 ubiquitin ligase complex that contains the von Hippel-Lindau tumor suppressor protein (pVHL), elongin B, elongin C, Cul2, and Rbx1 (also called ROC1 or Hrt1)