Modeling hypoxia stress response pathways

Abstract

Summary form only given. Hypoxic stress is a consequence of the decrease in oxygen reaching the tissues of the body. Oxygen is essential for energy production, since it is the terminal electron acceptor in the Electron Transport Chain (ETC) of the mitochondria. This makes the condition of low oxygen availability (hypoxia) deleterious to living cells and proper adaptation techniques must be employed by the cell for survival. The main sensors for cellular partial pressure alterations and hypoxia are three hydroxylases, known as prolyl hydroxylase domain containing proteins (PHDs) namely PHD1, PHD2 and PHD3. They initiate a cascade of cell signaling through a family of transcription factors appropriately named as Hypoxia Inducible factor (HIF). There are currently three members HIF-1, HIF-2 and HIF-3, each of them is an HIF heterodimer, possessing α and β factor subunits coded by 6 genes (HIF1α, ARNT (Aryl Hydrocarbon Nuclear Translocator), EPAS1 (Endothelial PAS domain containing protein 1), ARNT2, HIF3α and ARNT3 respectively). When enough oxygen is available, the proline residue in the Oxygen Dependent Degradation (ODD) domain of HIF-1α undergoes non-reversible hydroxylation in the presence of PHD2. During normoxia, HIF-1α is hydroxylated by PHD2, and the hydroxylated HIF-1α interacts with von Hippel-Lindua tumor suppressor protein (VHL) and is degraded by ubiquitination. But during hypoxia, PHD2 is inhibited which results in HIF-1α stabilization. Stabilized HIF-1α enters the nucleus and heterodimerizes with HIF-1β and binds the DNA via the Hypoxia Response Elements (HRE) within the promoter regions of the target genes. HIF-regulated target genes enable cells to induce an adaptive response by increasing glycolysis, angiogenesis and other patho-physiological events or undergo cell death by promoting apoptosis or necrosis. The decision of adaptation or cell death depends on the extent of hypoxic stress faced by the cells. The adaptive response during hypoxic stress is mainly observed in solid tumors, where the increased demand for oxygen is met by the up-regulation of genes involved in angiogenesis, vasculogenesis, glycolysis and other physiological events. Hence, proper understanding of hypoxia stress response pathway is critical for understanding the mechanism of tumor cell adaptation to hypoxia and to develop efficient therapeutic interventions. Using prior knowledge of hypoxia stress response pathways from the literature, a Boolean model of it is developed and simulated. This model allows for a better understanding of the perturbations of hypoxia response, which is derived from complex multivariate interactions of biological molecules.