Cytokines and Hormones in the Regulation of Hypoxia Inducible Factor-1α (HIF-1α)

Jie      Zhou; Bernhard      Brune

Abstract

Hypoxia inducible factor-1 (HIF-1) is a central component of the oxygen sensing system that coordinates cellular responses to conditions of decreased oxygen availability. The hypoxia inducible transcription factor HIF-1 is a heterodimer composed of the helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF-1alpha and the aryl hydrocarbon nuclear translocator (ARNT) also known as HIF-1beta. Transactivation of HIF-1 transmits a hypoxic signal into pathophysiological responses such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, as well as cell survival decisions by regulating a staidly growing number of target genes. Among recent advances are the discoveries that cytokines and growth factors make use of the hypoxic signaling system under normoxia. Here we summarize current knowledge and existing concepts that help to understand how cytokines and hormones affect protein accumulation of HIF- 1alpha and discuss potential implications of activating HIF-1 under normoxia. Considering the fundamental role of cytokines during inflammation may predict a role of HIF-1alpha in coordinating cellular responses to pathogens and point to the connection of cancer and inflammation. Moreover, we will address potential feed-back mechanisms showing an impact of HIF-1 on cytokine production. These considerations suggest an intimate signaling cross-talk between cytokines and the HIF-1 system.

Keywords: Hypoxia, proteasome, protein translation, PI3K/Akt, NF-κB, MAPK, ROS