The Hypoxic Response: Huffing and HIFing

With the convergence of several independent areas of hypoxia research on a common oxygen sensing pathway, HIF-1 has emerged as a central regulator of hypoxic gene expression and restoration of cellular oxygen homeostasis. A working model for the pathway is schematized in Figure 1Figure 1. Oxygen directly interacts with the cellular oxygen sensor independently of mitochondrial respiration, keeping the sensor inactive. When oxygen levels drop, the deoxy form of the sensor activates a signal that may then be transduced via protein phosphorylation to factor X, which leads to increased expression of HIF-1α and -1β. The HIF-1 heterodimer in turn induces a battery of genes involved in cellular and global responses to hypoxia including anaerobic metabolism, erythropoiesis, angiogenesis, and breathing, which allows the cell to survive at low oxygen and helps restore the normal oxygen level.Although all cells apparently contain the same general pathway, the end response in each cell type is individually tailored. Thus while most cells exposed to prolonged hypoxia will induce expression of glycolytic genes and various angiogenic factors, only cells of the liver and kidney induce EPO. HIF-1 must therefore function combinatorially with cell type–specific regulatory factors like the orphan receptor HNF-4 (see legend of Figure 1Figure 1) to control these specific responses. Further levels of control and feedback in the pathway may be provided by posttranscriptional regulation of HIF-1, because the turnover of HIF-1 transcripts and proteins is sensitive to hypoxia, and the phosphorylation and redox state of HIF-1 protein can influence its activity (Wang et al. 1995axWang, G.L., Jiang, B.H., Rue, E.A., and Semenza, G.L. Proc. Natl. Acad. Sci. USA. 1995; 92: 5510–5514Crossref | PubMed | Scopus (3500)See all ReferencesWang et al. 1995a18xWang, G.L., Jiang, B.H., and Semenza, G.L. Biochem. Biophys. Res. Commun. 1995; 216: 669–675Crossref | PubMed | Scopus (184)See all References, 14xSemenza, G.L. Trends Cardiovasc. Med. 1996; 6: 151–157Abstract | Full Text | Full Text PDF | PubMed | Scopus (78)See all References).While an outline of the HIF-1 hypoxic response pathway is emerging, many critical questions remain. What are the identities of the cellular oxygen sensor and factor X, and what is the mechanism of signaling between these two parts of the pathway? What are the other hypoxic regulators that work in conjunction with or independently of HIF-1? We also need to better understand the full range of cellular responses to low oxygen tensions and how a cell coordinates the HIF-1 pathway with other hypoxic responses such as the Pasteur effect, the shutdown of nonessential cell functions, and the most severe response, the induction of cellular suicide by p53-mediated apoptosis (Graeber et al. 1996xGraeber, T.G., Osmanian, C., Jacks, T., Housman, D.E., Koch, C.J., Lowe, S.W., and Giaccia, A.J. Nature. 1996; 379: 88–91Crossref | PubMed | Scopus (1884)See all ReferencesGraeber et al. 1996). Such an understanding would facilitate the development of medical treatments for rescuing ischemic tissues and for destroying tumor cells.While rapid progress is likely to continue with the current biochemical and molecular biological approaches, other tacks may be needed to piece together the entire HIF-1 pathway. Hypoxia pathways are being worked out in the yeast Saccharomyces cerevesiae (Zitomer and Lowry 1992xZitomer, R.S. and Lowry, C.V. Microbiol. Rev. 1992; 56: 1–11PubMedSee all ReferencesZitomer and Lowry 1992), but they differ in a number of respects from the HIF pathway, and indeed the S. cerevesiae genome lacks HIF-1 homologs. Drosophila may allow a traditional genetic approach because flies and other insects exhibit characteristic responses to hypoxia, including induction of glycolytic genes and a proliferation of the tracheal branches that deliver oxygen to the tissues (Manning and Krasnow 1993xManning, G. and Krasnow, M.A. : 609–685See all ReferencesManning and Krasnow 1993), and Drosophila cell extracts contain a HIF-1-like DNA binding activity (Nagao et al. 1996xNagao, M., Ebert, B.L., Ratcliffe, P.J., and Pugh, C.W. FEBS Lett. 1996; 387: 161–166Abstract | Full Text PDF | PubMed | Scopus (44)See all ReferencesNagao et al. 1996). Certain inherited human diseases might also provide insights into hypoxic signaling. For example, several families have been identified with consitutively high EPO levels, and some of these could be due to mutations that cause constitutive activity of the HIF-1 pathway. Given the energetic pace of the field and the pressing medical need to understand the hypoxic response, we shouldn't have to hold our breath long for answers.