| The ability of cells to adapt to changes in oxygen (O2) levels is essential for normal development and physiology. O2 deprivation can occur in a number of settings, in particular, during myocardial infarction and acute ischemia such as stroke. The hypoxia-inducible transcription factor (HIF) complex plays an important role in the induction of many genes with diverse functions in cells that experience a shortage of O2. These include glucose transporters and glycolytic enzymes, as well as growth factors required for angiogenesis and erythropoiesis. The HIF complex consists of a HIF-alpha and HIF-beta dimer. To date, three HIF-alpha and three HIF-beta subunits have been identified. HIF-1alpha and HIF-2alpha share a high degree of sequence identity. In addition, both HIF-1alpha and HIF2alpha are regulated by O2 deprivation in that they are rapidly degraded by their interaction with the von Hippel-Lindau protein (pVHL) during normoxia and stabilized under hypoxia. Finally, both proteins can activate transcription of HRE-containing genes. However, expression patterns, knockout phenotypes, and tumorigenesis studies suggest unique roles for HIF-1alpha and HIF-2alpha. The degree to which these functions of HIF-1alpha and HIF-2alpha are a consequence of different tissue-specific expression patterns or of unique target gene activation is unknown. Using a genetic "knock-in" strategy, I have demonstrated that targeted replacement of HIF-1alpha with HIF-2alpha causes severe developmental defects and promotes tumor growth. These phenotypes are caused in part by expanded expression of HIF-2alpha target genes, including TGF-alpha and Oct-4, a transcription factor essential for maintaining stem cell pluripotency. Oct-4 is a novel HIF-2alpha target, and I have shown that HIF-2alpha activation of Oct-4 is important for primordial germ cell development and HIF-2alpha's tumor promoting activity. These data provide the initial connection between hypoxia (HIF-2alpha) and a factor critical for stem cell maintenance (Oct-4) and provides novel insight into the regulation of stem cells in normal development and tumor progression. Finally, these data suggest that targeting HIF-2alpha activity may be a useful strategy for modulating stem cell function, and possibly cancer stem cell differentiation, through alteration of Oct-4 expression. |
