The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease

Abstract

The ability to sense and respond to changes in oxygen is essential for the survival of prokaryotic and eukaryotic organisms. Oxygen-sensing mechanisms have been developed to maintain cell and tissue homeostasis, as well as to adapt to the chronic low-oxygen conditions found in diseases such as cancer. This report on the first Keystone Meeting on the Biology of Hypoxia will summarize our current understanding of key genes and pathways involved in oxygen sensing that are required for normal development and that are dysregulated in disease states. It will also comment on future directions for this exciting field.

Figure 1.

Physiologic response pathways to hypoxia. For details, see text.

Figure 2.

Mechanisms of HIF-1α regulation under aerobic and hypoxic conditions. Under aerobic conditions, HIF-1α is hydroxylated on proline 402 and proline 564. The proline hydroxylations are necessary for binding to VHL and ubiquitin-mediated degradation by the proteasome. The asparagine hydroxylation prevents binding to p300/CBP. A splice derivative of HIF-3α called IPAS, as it only possesses the PAS domain, competes for HIF-1β binding. The TAD of HIF-1α binds p300/CBP and other coactivators such as SRC-1. HIF-1α and HIF-1β both translocate to the nucleus to transactivate genes such as VEGF that possess hypoxia responsive elements (HREs).