Identification of unique HIF-alpha function in tumorigenesis and development.

摘要

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.